Methods of neuromodulation using infraslow stimulation

ABSTRACT

Methods are provided to treat a neurological disorder in a patient by adjusting connectivity between network nodes in a brain of patient using electrical stimulation. Electrical stimulation including a carrier wave component is employed to adjust connectivity using infraslow frequencies of less than 1 Hz.

RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 15/585,984 filed May 3, 2017 which is a continuation-in-part ofU.S. patent application Ser. No. 14/851,540, filed Sep. 11, 2015 whichclaims priority to U.S. Patent Provisional Application Ser. No.62/049,086 filed Sep. 11, 2014. application Ser. No. 15/585,984 is acontinuation-in-part of U.S. patent application Ser. No. 15/078,819,filed Mar. 23, 2016 which claims priority to U.S. Patent ProvisionalApplication Ser. No. 62/137,587 filed Mar. 24, 2015. application Ser.No. 15/585,984 also claims priority to U.S. Patent ProvisionalApplication Ser. No. 62/331,314 filed May 3, 2016. All of theseapplications are incorporated herein by reference in their entirety.

BACKGROUND

NS systems are devices that generate electrical pulses and deliver thepulses to nervous tissue to treat a variety of disorders. For example,spinal cord stimulation has been used to treat chronic and intractablepain. Another example is deep brain stimulation, which has been used totreat movement disorders such as Parkinson's disease and affectivedisorders such as depression. SCS therapy, delivered via epidurallyimplanted electrodes, is a widely used treatment for chronic intractableneuropathic pain of different origins. Traditional tonic therapy evokesparesthesia covering painful areas of a patient. During SCS therapycalibration, the paresthesia is identified and localized to the painfulareas by the patient in connection with determining correct electrodeplacement.

Recently, new stimulation configurations such as burst stimulation andhigh frequency stimulation, have been developed, in which closely spacedhigh frequency pulses are delivered. In general, conventionalneurostimulation systems seek to manage pain and other pathologic orphysiologic disorders through stimulation of select nerve fibers thatcarry pain related signals. However, nerve fibers and brain tissue carryother types of signals, not simply pain related signals.

Although some neurological disorders have been treated through knownneurostimulation methods, many other neurological disorders exhibitphysiological complexity, functional complexity, or other complexity andhave not been adequately treated through known neurostimulation methods.

SUMMARY

In accordance with embodiments disclosed herein, optimal targets withinthe nervous system are selected for neuromodulation. The optimal targetsare selected according to network connectivity within the nervous systemof a patient according to selected embodiments. For example, the brainof a patient may be modeled as a complex adaptive system of one or moreneural networks. The brain may be viewed as exhibiting small worldtopology characteristics. That is, the brain functions as a modularscale free hierarchical network (e.g., fractal in organization). Also,the brain functions in the presence of noise (equivalently variabilityin neural activity). In a noisy, hierarchical organization, the brainfunctions as a complex adaptive network of interconnected modules. Byselecting one or more nodes within one or more networks within the brainfor stimulation, a neurological disorder may be treated by strengtheningor weakening the network connectivity to treat an identifiedneurological disorder.

Certain connectivity between neural populations in the brain may bedefined by structural connectivity. The structural connectivity may bedetermined using diffusion tensor imaging (DTI), diffusion spectrumimaging (DSI) or diffusion kurtosis imaging (DKI) as examples.Connectivity may also be the result of functional connectivity in anetwork. The functional connectivity may be determined by correlation inneural activity in one or more respective brain areas or brain networks.Also, connectivity may be related to effective connectivity, which canbe considered directional functional connectivity, through the result ofinformation transfer between neural nodes and networks.

Improper connectivity from a neurological disorder is addressedaccording to embodiments disclosed herein. In some embodiments,insufficient or decreased functional and/or effective connectivityrelated to a neurological disorder is strengthened by simultaneous orotherwise synchronized stimulation in two or more nodes of one or moreneural networks relevant to the neurological disorder or by burststimulation in a single hub of a network In some embodiments, excessivefunctional and/or effective connectivity related to a neurologicaldisorder is weakened by asynchronous or randomized stimulation in one ormore hubs of a neural network relevant to the respective neurologicaldisorder.

In a network connectivity framework, the centrality of a node refers tohow many of the shortest paths between all other node pairs in a networkpass through the respective node. As discussed herein, a hub refers to anetwork node in a neurological network which exhibits a high degree ofcentrality. Neurological hubs connect to may other brain areas. “Richclub” neurological sites refer to neurological sites that are hubs andare connected to many other hubs. Rich club sites integrate neurologicalactivity from different networks and different neurological modules.

According to some embodiments, sites for neuromodulation are selectedaccording to identified hubs (for example feeder hubs or hubs of therich club or core) By selecting hub and rich club sites, improperconnectivity (associated with a given neurological disorder) can be moreeffectively strengthened or weakened depending upon the specificneurological disorder.

In some embodiments, network stimulation may include stimulation of oneor more peripheral nerves, autonomic nerves (vagal, sympathetic nerves),sensory nerves, auditory nerves, and/or the spinal cord, in addition tostimulation of sites in the brain.

Multiple types of stimulation patterns may be employed for networkstimulation according to respective embodiments including tonic, burst,and noise stimulation patterns as examples.

In some embodiments, nested stimulation may be provided to one or morenodes within one or more neural networks in association with adjustingconnectivity within or between one or more networks. Details regardingnested stimulation may also be found in U.S. patent application Ser.Ser. No. 14/851,540, entitled “SYSTEM AND METHOD FOR NESTEDNEUROSTIMULATION,” which is incorporated herein by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates an example neurological stimulation (NS) system forelectrically stimulating a predetermined site area to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 1B illustrates an example neurological stimulation (NS) systems forelectrically stimulating a predetermined site area to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 1C depicts an NS system that delivers stimulation therapies inaccordance with embodiments herein.

FIG. 2A illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2B illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2C illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2D illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2E illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2F illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2G illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2H illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2I illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 3 illustrates an example of the various brainwave frequency bandsin accordance with embodiments herein.

FIGS. 4A-4G illustrate examples of cross frequency coupling variationsthat may be used in accordance with embodiments herein.

FIG. 5 illustrates a model of a portion of the brain with interestdirected to neural modules in accordance with embodiments herein.

FIG. 6 illustrates a model reflecting the memory functionality of abrain in accordance with embodiments herein.

FIG. 7A illustrates models proposed, in the 2007 Jensen paper, regardingcomputational roles for cross-frequency interactions between theta andgamma oscillations by means of phase coding in accordance withembodiments herein.

FIG. 7B illustrates models proposed, in the 2007 Jensen paper, regardingcomputational roles for cross-frequency interactions between theta andgamma oscillations by means of phase coding in accordance withembodiments herein.

FIG. 7C illustrates cross-frequency interactions including infra-slowwave oscillations in accordance with embodiments herein.

FIG. 8A illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein.

FIG. 8B illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein.

FIG. 8C illustrates an alternative example of a nested stimulationwaveform that may be delivered in connection with nested therapies tobrain tissue (or brain tissue) of interest in accordance withembodiments herein.

FIGS. 9A-9F illustrate alternative nested stimulation waveforms that maybe utilized in accordance with embodiments herein.

FIG. 10 illustrates leads implanted for stimulation of neural networksto adjust connectivity according to embodiments herein.

FIG. 11 illustrates stimulation of the reward network in conjunctionwith adjusting network connectivity according to embodiments herein.

FIG. 12 illustrates leads implanted for stimulation of neural networksto adjust connectivity to treat tinnitus according to embodimentsherein.

FIG. 13 depicts a stimulation lead (hippocampal-cortical memory system(HCMS)) over region 1311 and a stimulation lead over region 1312(frontoparietal control system (FPCS)) to deliver neurostirnulationaccording to some embodiments.

DETAILED DESCRIPTION

While multiple embodiments are described, still other embodiments of thedescribed subject matter will become apparent to those skilled in theart from the following detailed description and drawings, which show anddescribe illustrative embodiments of disclosed inventive subject matter.As will be realized, the inventive subject matter is capable ofmodifications in various aspects, all without departing from the spiritand scope of the described subject matter. Accordingly, the drawings anddetailed description are to be regarded as illustrative in nature andnot restrictive.

I. Definitions

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. For purposes of thedescription, the following terms are defined below. Further, additionalterms are used herein that shall have definitions consistent with thedefinitions set forth in U.S. Pat. No. 8,401,655, which is expresslyincorporated herein by reference in its entirety.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification maymean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having”, “including”, “containing” and “comprising” are interchangeableand one of skill in the art is cognizant that these terms are open endedterms.

As used herein, the term “burst firing” or “burst mode” refers to anaction potential that is a burst of high frequency spikes/pulses (e.g.400-1000 Hz) (Beurrier et al., 1999). Burst firing acts in a non-linearfashion with a summation effect of each spike/pulse. One skilled in theart is also aware that burst firing can also be referred to as phasicfiring, rhythmic firing (Lee 2001), pulse train firing, oscillatoryfiring and spike train firing, all of these terms used herein areinterchangeable.

As used herein, the term “tonic firing” or “tonic mode” refers to anaction potential that occurs in a linear fashion.

As used herein, the term “burst” refers to a period in a spike trainthat has a much higher discharge rate than surrounding periods in thespike train (N. Urbain et al., 2002). Thus, burst can refer to aplurality of groups of spike pulses. A burst is a train of actionpotentials that, possibly, occurs during a ‘plateau’ or ‘active phase’,followed by a period of relative quiescence called the ‘silent phase’(Nunemaker, Cellscience Reviews Vol 2 No. 1, 2005.) Thus, a burstcomprises spikes having an inter-spike interval in which the spikes areseparated by 0.5 milliseconds to about 100 milliseconds. Those of skillin the art realize that the inter-spike interval can be longer orshorter. Yet further, those of skill in the art also realize that thespike rate within the burst does not necessarily occur at a fixed rate;this rate can be variable.

The terms “pulse” and “spike” are used interchangeably to refer to anaction potential. Yet further, a “burst spike” refers to a spike that ispreceded or followed by another spike within a short time interval(Matveev, 2000), in other words, there is an inter-spike interval, inwhich this interval is generally about 100 ms but can be shorter orlonger, for example 0.5 milliseconds.

In accordance with embodiments disclosed herein, the brain of a patientis modeled as a complex adaptive system of one or more neural networks.The brain may be viewed as exhibiting small world topologycharacteristics. That is, the brain functions as a modular scale freehierarchical network (e.g., fractal in organization). Also, the brainfunctions in the presence of noise (equivalently variability in neuralactivity)—see, for example, U.S. Pat. No. 8,682,441 by De Ridder, whichis incorporated herein by reference. In a noisy, hierarchicalorganization, the brain functions as a complex adaptive network ofinterconnected modules. By selecting multiple nodes within one or morenetworks within the brain for stimulation, a neurological disorder maybe treated by strengthening or weakening the network connectivity withina single network or between multiple networks. The nodes forneuromodulation are selected according to network hubs and/or rich clubsites according to some embodiments.

Certain connectivity between neural populations in the brain may bedefined by structural connectivity. The structural connectivity may bedetermined using diffusion tensor imaging (DTI) or diffusion spectrumimaging (DSI) as examples.

Connectivity may also be the result of functional connectivity in anetwork. The functional connectivity may be determined by correlation inactivity in one or more respective networks using multiple electrodes todetect neural activity in relevant brain locations. Any number ofsuitable mechanisms may be employed to measure neuronal activity forsuitable processing.

For example, EEG (or electroencephalogram) is a recording of brainwaveactivity. QEEG (Quantitative EEG), popularly known as brain mapping,refers to a comprehensive analysis of brainwave frequency bandwidthsthat make up the raw EEG. QEEG is recorded the same way as EEG, but thedata acquired in the recording are used to create topographiccolor-coded maps that show electrical activity of the cerebral cortex.

In an QEEG analysis, the electrical activity of the brain is measured byplacing a number of electrodes or sensors about the head of a patientand the sensors are connected to a recording device. Electrical activityis recorded using the sensors for typically ten to thirty minutes.

The data representing the recorded electrical activity is suitablyprocessed. The processing provides complex analysis of brainwavecharacteristics such as symmetry, phase, coherence, amplitude, power anddominant frequency. Such processing enables the correlation, coherence,and relevant activity metrics indicative of functional connectionbetween brain locations to be identified.

The analysis enables activity falling above or below a statistical normto be identified for locations within the brain. Also, the activity mayidentify activity above or below the norm for relevant brainwavefrequency bands (delta, theta, alpha, beta, and gamma bands asexamples). The activity variance from the norm can be expressed relativeto a calculated standard deviation of activity data.

Further, the QEEG analysis further enables functional connectivity to beidentified by coherence analysis of activity between different neuralsites. The functional connectivity can be likewise expressed in terms ofabove or below the norm relative to a standard deviation calculation.

Additional and/or alternative processing of recordings of electricalactivity in the brain of a patient may be employed to assistidentification of variations in functional connectivity related to aneurological disorder according to some embodiments. For example, QEEGcombined with LORETA (Low Resolution Electromagnetic Tomography) enablesexamining of deep structures of the brain slice by slice, as well asviewing 3-dimensional models of the brain and may provide a suitableanalysis to identify functional connectivity resulting from aneurological disorder to be treated according to representativeembodiments.

Also, the BrainWave software application (available from the Departmentof Clinical Neurophysiology, VU University Medical Center, Amsterdam,The Netherlands) is an application for the analysis of multivariateneurophysiological data sets (such as EEG data sets). The BrainWaveapplication provides several measures of functional connectivity(coherence, phase coherence, imaginary coherence, PLI andsynchronization likelihood) among other relevant neural activitymetrics. The functional connectivity mapping of the BrainWaveapplication may be employed to assist identification of variations infunctional connectivity related to a neurological disorder in a patientaccording to some embodiments.

In some embodiments, a network representation of neural activity iscreated using graph and network concepts. The graph representation maybe patterned according to a mathematical representation of a neuralnetwork composed of interconnected elements or sites. The representationmay involve construction and processing according to Graph Theory(mathematical study of graphs/networks). From the representation, thenetwork topology of the neural activity may be analyzed according tomathematical analysis of shapes and spaces, concerned with the invariantproperties of space that are preserved under continuous deformations(bending, stretching). Also, topological distance does not necessarilyimply close physical distances. Thus, physical distances between nodes,transmission rates, and/or signal types may differ in two networks andyet their topologies may be identical.

Hubs are nodes with high degree (or high centrality). The degree of anode is the number of connections that link it to the rest of thenetwork. Degrees of all the network's nodes form a degree distribution.Assortativity is the correlation between the degrees of connected nodes.Positive assortativity indicates that high-degree nodes tend to connectto each other (rich club). Clustering coefficient quantifies the numberof connections that exist between the nearest neighbors of a node as aproportion of the maximum number of possible connections. Path length isthe minimum number of edges that must be traversed to go from one nodeto another. Each module contains several densely interconnected nodes,and there are relatively few connections between nodes in differentmodules. Connection density is the actual number of edges in the graphas a proportion of the total number of possible edges and is thesimplest estimator of the physical cost. Connection density is anindirect measure of global efficiency. Centrality of a node measures howmany of the shortest paths between all other node pairs in the networkpass through it.

Most brain disorders are hub disorders. For example, lesions in neuralhubs are linked to amyotrophic lateral sclerosis, dystonia,developmental dyslexia, anorexia nervosa, obsessive-compulsive disorder,Parkinson's disease, hereditary ataxia, dementia in Parkinson's, chronicpain, panic disorder, attention deficit hyperactivity disorder, bipolaraffective disorder, multiple sclerosis, frontotemporal dementia,obstructive sleep apnea, Autism, schizophrenia, Alzheimer's disease,Asperger syndrome, Huntington's disease, depressive disorder, righttemporal lobe epilepsy, post traumatic stress disorder, progressivesupranuclear palsy, left temporal lobe epilepsy, and juvenile myodonlcepilepsy. Accordingly, representative embodiments employneurostimulation of one or more hubs (possibly rich club sites or feederhubs) to treat any of the neurological disorders discussed herein.

One or more hubs and/or rich club sites associated with a respectiveneurological disorder in a patient may be identified from therepresentation of neural activity generated by the measurement andprocessing operations discussed herein. The activity and cross-couplingbetween nodes, hubs, and/or rich club sites may be identified andcompared to activity and coupling exhibited by healthy controls.Relevant deviations from the healthy controls are used to identifyneural hubs and/or rich club sites for neuromodulation to treat therespective neurological disorder.

Improper neural connectivity (associated with neural hubs and rich clubor core sites) as detected using the operations discussed herein isaddressed using neuromodulation of identified sites. As previouslydiscussed, various EEG, MEG or functional MRI measurements andprocessing may be employed to analyze coupling associated withrespective hubs. Coupling between respective sites may be identified,for example, in reference to envelope correlation of neural activity atthe various neural sites. The improper coupling can be treated byrecoupling and uncoupling as appropriate for a given neurologicaldisorder. In some embodiments, insufficient functional and/or effectiveconnectivity related to a neurological disorder is strengthened bysimultaneous or otherwise synchronized stimulation in relevant sites. Insome embodiments, excessive functional and/or effective connectivityrelated to a neurological disorder is weakened by asynchronous orrandomized or noise stimulation in relevant sites. The treatmentmethodology may also monitor the effectiveness of the therapy bydetermining whether connectivity is modified after stimulation usingsuitable activity measurement techniques and processing.

In some embodiments, functional connectivity may be strengthened byapplying burst stimulation using a single electrode or electrodecombination to stimulate relevant hub neurons. Burst stimulation of ahub site will trigger synchronous firing across the neural networkcontaining the respective hub site. Also, burst stimulation may beapplied simultaneously to two or more separate sets of electrodes in twoor more hub or non-hub areas. The synchronization of burst stimulationin this manner will cause the neural connection between the two sites tobe rewired and strengthened. Hub stimulation using this methodology maybe use to treat traumatic brain injury and postconcussion syndrome andto prevent dementia pugilistica as examples. For example, suitable burststimulation may be applied to a suitable thalamus site to strengthenfunctional connectivity in such patients.

In some embodiments, functional connectivity may be reduced by applyingnoise stimulation using a single electrode or electrode combination tostimulate relevant hub neurons functionally connected to a neuralnetwork associated with a relevant neurological disorder. For example,functional connectivity may arise in addiction disorders. Neuralactivity in the dACC becomes functionally coupled to activity in thePCC. Activity in these areas are normally anticorrelated. The functionalconnectivity caused by the addiction disorder may be treated by noisestimulation in the dACC or PCC. Alternatively, noise stimulation in thedACC and burst stimulation in the PCC may be applied to treat addictionin some embodiments. These techniques for dACC and PCC stimulation toadjust functional connectivity may also be employed to treat patientswith depression and/or anxiety disorders.

In some embodiments, hub stimulation is applied to a patientspecifically to generate anticorrelated activity in respective areas ofthe brain. In some neurological disorders such as loss of consciousness,addiction, OCD, chronic pain, tinnitus, etc., there is less or no moreanticorrelated activity between two or more networks. Most commonly,this reduction or lack of anticorrelated activity is exhibited betweenthe default mode network and the salience network, but it also occursbetween other areas such as the dorsal ACC and pregenual ACC. By usingburst stimulation and noise stimulation simultaneously in the respectivenetworks that need to become anticorrelated, the underlying neurologicaldisorder is treated according to some embodiments. In these embodiments,one or more hubs in the default mode network are selected forstimulation such as posterior cingulate cortex (PCC) and precuneus.Also, one or more hubs in the salience network are selected forstimulation such as the anterior cingulate cortex (ACC) and insula.Using electrodes implanted at these sites, burst stimulation is appliedfor 10 seconds (for example) to the PCC and simultaneous noisestimulation applied to the ACC followed by 10 seconds of bursting in ACCand simultaneous noise stimulation in the PCC. This repetition of noiseand burst in the respective areas is then repeated over an appropriateamount of time. This stimulation pattern induces or promotesanticorrelated activity in the two networks (default mode network andsalience network). This stimulation methodology is believed to benefitpatients with addiction, OCD, pain, tinnitus, etc. Also, thisstimulation methodology may be employed to assist patients in a coma, avegetative state or a minimal conscious state to regain consciousness.

In some embodiments, functional connectivity may be modified by applyingsuitable stimulation to the nucleus accumbens and other relevant sites.For example, respective electrodes may be employed to stimulate nucleusaccumbens and pregenual ACC and/or vmPFC sites to adjust functionalconnectivity to treat relevant neurological disorders including OCD.Stimulation of pgACC and accumbens sites to adjust functionalconnectivity may be employed to treat patients with chronic pain.

FIG. 10 depicts a patient with implanted cortical leads 1001 and 1002.Lead 1001 is disposed over region 1011 and lead 1002 is disposed overregion 1012. One or both of regions 1011 and 1012 may be a hub and/or arich club neural site within a neurological network. The variouselectrodes of leads 1001 and 1002 may be employed to deliver electricalpulses to appropriate sites within regions 1011 and 1012. For aneurological disorder that exhibits weakened functional connectivitybetween a first site within region 1011 and a second site within region1002, repetitive synchronous stimulation of the first site and thesecond site will increase the functional connectivity between thesesites. For example, the synchronous stimulation may involve repetitivelyproviding a stimulation pulse to the first site and then providing astimulation pulse to the second site with a defined delay relative tothe first site. The repetition of providing synchronized stimulationpulses may occur at suitable frequencies from 0.01 to 600 Hz, but mostcommonly between 0.1 Hz and 40 Hz. Tonic, burst stimulation, nestedstimulation, and the suitable stimulation patterns may be applied withsuitable synchronization. For a neurological disorder that exhibitsexcessive functional connectivity between a first site within region1011 and a second site within region 1012, random or asynchronousstimulation patterns may be applied via suitable electrodes of leads1001 and 1002. Although two sites are described herein, networkstimulation may include stimulation of three or more network nodesaccording to embodiments described herein.

Brain function depends on activity in multiple parallel networks andsome subsets of parallel networks function in an anti-correlated manner.That is, one network is active and simultaneously the other network isinactive when the brain is functioning properly. When disease or injuryoccurs, the anti-correlation between activity in certain networks may bereduced or disappear. Anticorrelation can occur at differentfrequencies, between 0.01 and 600 Hz, but most commonly between 0.1 and40 Hz.

In some embodiments, hub stimulation is augmented by stimulation of thereward system. Suitable locations within the reward system forstimulation may include one or more locations selected from the listconsisting of: the nucleus accumbens (NAc), caudate nucleus, thelaterodorsal tegmentum, ventral tegmental area (VTA), the ventralpallidum, the subthalamic nucleus (STN), medial dorsal nucleus of thethalamus, and the posterior cingulate cortex (PCC). as well as theventral tegmental area, pregenual, rostral or dorsal anterior cingulatecortex, as well as the anterior and/or posterior insula or the fiberbundles connecting either of these areas. Additional details regardingstimulation of the reward network of a patient may be found in U.S.Provisional Patent Application Ser. No. 62/007,058, entitled “METHOD OFTREATING A NEUROLOGICAL DISORDER IN A PATIENT (RECONDITIONING)” filedJun. 3, 2014, which is incorporated herein by reference.

Stimulation of a suitable site in the reward network of a patient inconjunction with strengthening or weakening network connectivity betweenother network sites facilitates a permanent change in the connectivitybetween those network sites. Specifically, a conditioning effect occursto retain the desired modification in connectivity. In some embodiments,a burst stimulation pattern is applied to a nucleus accumbens site, aPCC site, or a caudate nucleus site to generate the conditioning effect.

FIG. 11 depicts stimulation of neuronal sites within the reward networkof a patient according to some embodiments. In FIG. 11, burststimulation 1101 is provided to the nucleus accumbens. This couldinclude clustered high frequency stimulation, e.g. 5 to 100 individuallycharge balanced pulses delivered at 100-500 Hz. Optionally, highfrequency stimulation 1102 (e.g., approximately 100 Hz or greater) isprovided to lateral habenula the while burst stimulation 1101 isprovided to the nucleus accumbens. Stimulation 1102 blocks activity ofthe lateral habenula, either by disrupting habenula activity or bydriving habenula activity at specific frequencies from providing inputto the VTA while input from the nucleus accumbens to the VTA occurs (asa result of burst stimulation 1101). The stimulation within structuresof the reward network are provided to the patient immediately after orsimultaneous with or immediately before stimulation is provided, as longas it is consistently associated, to adjust connectivity within one ormore neural networks of the patient according to some embodiments.

In some embodiments, network stimulation may include stimulation of oneor more peripheral nerves, autonomic nerves (vagal, sympathetic nerves),sensory nerves, auditory nerves, and/or the spinal cord, in addition tostimulation of sites in the brain.

In certain embodiments, network stimulation is used to treatneurological disorders involving stress, salience, and distressprocesses in a patient. In relevant neurological disorders, increasedfunctional connectivity of the amygdala, dorsal anterior cingulatecortex (dACC), insula, and lateral cortex results in an extended stateof hypervigilance. This promotes sustained salience and mnemonicprocessing. For example, tinnitus/pain remains constant. It has beenobserved that tinnitus is exhibited in 50% of post-traumatic stressdisorder (PTSD), tortured patients. Randomized or otherwise asynchronousstimulation within multiple nodes within these networks may be employedto treat the neurological disorder.

FIG. 12 depicts functional connectivity graphs 1200 related to tinnitus.Connectivity graphs 1200 may be created by analyzing neural activity ofa patient to identify appropriate areas for neuromodulation according tosome embodiments. In some embodiments, the treatment methodologyinvolves identifying frequencies of neural activity associated withimproper neural network connectivity. Connectivity graphs 1200 representcorrelated neural activity at specific frequencies (10 Hz and 11.5 Hz),Also, connectivity graphs 1200 depict the connectivity for respectivelevels of tinnitus (severe/Grade 3 and very severe/Grade 4). As shown inFIG. 12, there is functional connectivity between the loudness networkand the distress network. Specifically, there is increased functionalconnectivity between parahippocampal cortex (PCC) and subgenual anteriorcingulate cortex (sgACC). Some representative embodiments treat tinnitusby stimulating respective sites in these two regions using randomized orasynchronous electrical stimulation.

In accordance with representative embodiments, hub stimulation isemployed to treat addiction-related neurological disorders. Repeated useof mood altering substances and other compounds may lead to unhealthyfunctional connectivity in neural networks in a patient. FIG. 13 depictsstimulation lead 1301 (hippocampal-cortical memory system (HCMS)) overregion 1311 and stimulation lead 1302 over region 1312 (frontoparietalcontrol system (FPCS)). In patients exhibiting neurological effects ofaddiction, regions 1311 and 1312 will often exhibit an unhealthy levelof functional connectivity. In representative embodiments, one or moreelectrodes of stimulation lead 1301 and one or more electrodes ofstimulation lead 1302 are employed to provide randomized or asynchronouselectrical stimulation of regions 1301 and 1302. The randomized orasynchronous electrical stimulation of these regions is believed toreduce or eliminate neurological processes related to the addiction ofthe patient. Addiction is but an example, as all reward deficiencysyndromes can potentially be treated with this embodiment. Rewarddeficiency syndromes include the brain disorders mentioned in the table(Blum, Molecular Neurobiology 2014)

TABLE 1 Reward deficiency syndrome behaviors (linked with DSM 5)Addictive behaviors Impulsive behaviors Obsessive Substance Nonsubstance Spectrum Disruptive compulsive Personality related relateddisorders impulsive behaviors disorders Alcohol Thrill seekingAttention-deficit Anti-social Body Paranoid (novelty) hyperactivitydysmorphic Cannabis Sexual sadism Tourene and tic Conduct HoardingSchizoid Syndrome Opioids Sexual masochism Autism IntermittentTrichotillomania Borderline explosive (hair pulling) Sedatives/Hypersexual Oppositional Excoriation Schizotypal hypnotics defiant (skinpicking) Stimulants Gambling Exhibionistic Non-suicidal Histrionicself-injury Tobacco Internet Narcissist gaming Glucose Avoidant FoodDependant

In accordance with representative embodiments, cognitive disorders mayresult in decrease functional connectivity within neural networks andbetween neural networks. For example, among the several conditionslabeled as dementia, the most common are Alzheimer's disease and mildcognitive impairment (MCI), which is a pre-clinical form of Alzheimer'sdisease. MCI is an intermediate state between normal aging and dementiaand is characterized by acquired cognitive deficits, without significantdecline in functional activities of daily living. Subjects with MCI andthe initial phase of Alzheimer's disease originally present with apredominant deficit in memory function. In more advanced stages ofAlzheimer's disease, impairment in addition cognitive domains culminateswith a significant decline in quality of life and the inability toperform usual daily activities. In patient's exhibiting dementia and/orMCI, suitable analysis of neural activity may be performed to identifynetwork node locations exhibiting improper connectivity. Synchronousstimulation of multiple sites may be employed to strengthen functionalconnectivity in such patients. For example, two, three, or more sites inthe posterior cingulate cortex, frontal and parietal cortex,parahippocampal area, hippocampus, and fornix or mammillary bodies maybe repetitively stimulated in sequence to increase functionalconnectivity.

Stimulation of multiple nodes in one network or in multiple networks toadjust connectivity between the nodes may be employed to treat a numberof neurological disorders. Neurological disorders involving excessiveconnectivity between distress neural network nodes and sensory networknodes (such as tinnitus and chronic pain) may be addresses using hubstimulation. Neurological disorders exhibiting diminished cognitiveabilities may benefit from hub stimulation (such as dementia, MCI, TBI,trauma disorders). Various network locations may be selected forstrengthening connectivity for such disorders (such as frontal cortexnetwork sites, memory network sites). Also, addiction disorders, eatingdisorders, and related disorders may be also be treated using suitablehub stimulation techniques as described herein.

In some embodiments, nested stimulation may be also applied to one ormore neural network sites to treat a neurological disorder of a patientwhen effecting functional connectivity between network nodes. Nestedstimulation according to respective embodiments stimulate neuronal sitesaccording to different types of physiological neural oscillations or“brain waves” across the cortex. The different types of neuraloscillation or brain wave activity can be decomposed into distinctfrequency bands that are associated with particular physiologic andpathologic characteristics.

FIG. 3 illustrates an example of the various brainwave frequency bandswhich include infraslow waves 302 (less than 1Hz, generally 0.001-1.0Hz, and 0.01-0.1 Hz in some embodiments); delta waves 304 (1-4Hz); thetawaves 306 (4-8 Hz); alpha waves 308 (8-12 Hz), beta waves 310 (12-30Hz), gamma waves 312 (greater than 30Hz), and sigma waves (not shown)(greater than 500Hz). Individual brainwave frequency bands andcombinations of brainwave frequency bands are associated with variousmental, physical and emotional characteristics. It should be recognizedthat the cutoff frequencies for the frequency bands for the varioustypes of brain waves are approximations. Instead, the cutoff frequenciesfor each frequency band may be slightly higher or lower than theexamples provided herein.

Neural oscillations from various combinations of the brainwave frequencybands have been shown to exhibit coupling with one another, wherein oneor more characteristics of one type of brainwave effect (or are affectedby) one or more characteristics of another type of brainwave. Ingeneral, the coupling phenomenon is referred to as cross frequencycoupling, various aspects of which are described in the papersreferenced herein. Combinations of frequency bands couple with oneanother to different degrees, while the coupling of various types ofbrainwaves may occur in connection with physiologic behavior orpathologic behavior. For example, theta and gamma frequency coupling hasbeen identified at the hippocampalcortical in connection withphysiologic behavior, but in thalamocortical activity this sametheta-gamma coupling should be considered pathological, as normalactivity consists of alpha-gamma coupling, except in sleep stagesDelta—gamma and delta—beta frequency coupling have been identified inconnection with physiological reward system activity as well as inautonomic nervous system activity. As another example, alpha—gammafrequency coupling has been identified at the pulvinar region inconnection with physiological processes mediating attention.

FIGS. 4A-4G illustrate examples of cross frequency coupling variationsthat may be used in accordance with embodiments herein. There aredifferent principles of cross-frequency interactions. FIGS. 4A-4Gillustrate various example brain waves 402-408. As one example, acarrier wave 402 may correspond to a slow oscillatory signal in thetheta band (e.g. 8 Hz). Although the frequency remains fairly constant,the power (as denoted by line 440) of the signal fluctuates over time.The gamma oscillations can interact in different ways with other signaloscillations.

The brain waves 403-408 illustrate examples of how the carrier andsecondary waves 402 and 403 may be combined. For example, the wave 403as illustrated, has been frequency coupled to the carrier wave 402 in apower to power matter such that the amplitude of the secondary wave 402reduces (as denoted at intermediate region 410) as the amplitude of thecarrier wave 402 reduces (as denoted in region 412). The amplitude ofthe secondary wave 403 is at a maximum in the regions 414 and 416corresponding to the maximum amplitudes of the carrier wave 402. Thefluctuations in power of the faster gamma oscillations are correlatedwith power changes in the lower frequency band. This interaction isindependent of the phases of the signals.

The brainwave 404 represents the carrier and secondary waves 402 and403, as frequency coupled in a phase to phase manner. Given that thecarrier and secondary waves 402 and 403 are aligned in phase with oneanother, the brainwave 404 exhibits a relatively even signal with littlenotable phase shift. Phase-locking occurs between oscillations atdifferent frequencies. In each slow cycle, there are four faster cyclesand their phase relationship remains fixed.

The brainwave 405 represents the carrier and secondary waves 402 and403, as frequency coupled in a phase to power manner. For example, theamplitude of the resulting brainwave 405 is modulated based on the phaseof the carrier wave 402. Accordingly, the brainwave 405 exhibits amaximum in amplitude in regions 418 which correspond to the positive 90°phase shift point (at reference numerals 420) in the carrier wave 402.The brainwave 405 exhibits a minimum amplitude in regions 422 whichcorrespond to the negative 90° phase shift point (at reference numerals424) in the carrier wave 402. Hence, in the example of brainwave 405,the amplitude of the higher frequency brainwave is modulated/determinedby the phase of the lower frequency carrier wave.

The brain waves 406-408 reflect the carrier and secondary waves 402 and403 when coupled in different manners, namely phase to frequency(brainwave 406), power to frequency (brainwave 407) and frequency tofrequency (brainwave 408). It is recognized that the brain wavesillustrated in FIGS. 4A-4G represent non-limiting examples and may beshaped in the numerous other manners. The different types ofcross-frequency interaction are not mutually exclusive. For instance,the phase of theta oscillations might modulate both frequency and powerof the gamma oscillations.

As explained herein, nested stimulation may be applied such that two,three or more frequency bands are coupled to one another to achievevarious results. As noted above, the lower band represents a carrierwave with higher frequency bands nested on the lower carrier wave. Thehigher frequency bands carry content to be utilized by the targetedneural modules. For example, the high-frequency content may besuperimposed into the phase of the lower carrier wave, such as inconnection with external information transmission. Alternatively, thehigh-frequency content may be added while maintaining phasesynchronization. Optionally, the high-frequency content may be addedthrough amplitude or frequency modulation to the lower carrier wave. Itis recognized that the high-frequency content may be added in othermanners as well, based on the particular neural region of interest anddesired effect that is being sought.

Nested stimulation according to some embodiments applies multiplefrequency bands to form a stimulation waveform or pattern. The waveformmay be analog waveform. Alternatively, the stimulation pattern mayinclude discontinuous pulses in other embodiments. The frequency bandsmay include respective bands from an infra-slow frequencies to sigmafrequencies.

The brain organization is shaped by an economic trade-off betweenminimizing costs and allowing efficiency in connection with adaptivestructural and functional topological connectivity patterns. Forexample, a low-cost, but low efficiency, organization would represent aregular lattice type topology. At an opposite end of the spectrum, arandom topology would be highly efficient, but be more economicallycostly.

FIG. 5 illustrates a model of a portion of the brain with interestdirected to neural modules 502 and 504. Local activity within modules502 and 504 generally exhibits high frequency brain waves/oscillations(as generally denoted by the links 506 and 508). For example, thehigh-frequency brain waves/oscillations may represent beta and gammawaves. The neural modules 502 and 504 communicate with one another overlong-distance communications links (as denoted at 510 and 512). Thecommunications links 510, 512 between distributed neural modules 502,504 occur through the use of low frequency brain waves (e.g. Delta,Theta and Alpha waves). The communication between modules 502, 504utilizes nesting or cross frequency coupling between the low frequencybrain waves (traveling between distributed neural modules) and the highfrequency brain waves (within corresponding neural modules). In thismanner, transient coherence or phase synchronization binds distributedneural assemblies/modules within the brain through dynamic (andpotentially long-range) connections. Nested therapy may be utilized tofacilitate long-distance communication links.

FIG. 6 illustrates a model reflecting the memory functionality of abrain. Memory has spatial and temporal characteristics 602 and 604.Memories are encoded through low frequency coupling betweenparahippocampal area 606, frontal area 608 and parietal (PFC) area 610.The spatial and temporal characteristics 602, 604 of memory aremultiplexed along common pathways through different frequencies. Forexample, the spatial characteristics 602 of memory are carried withinthe Delta wave frequency band, while the temporal characteristics 604 ofmemory are carried within the theta wave frequency band. Nested therapymay be utilized to facilitate spatial and/or temporal characteristicsfor memories.

FIGS. 7A and 7B illustrate models proposed, in the 2007 Jensen paper,regarding computational roles for cross-frequency interactions betweentheta and gamma oscillations by means of phase coding. FIG. 7Aillustrates a model for working memory, in which individual memoryrepresentations are activated repeatedly in theta cycles. Each memoryrepresentation is represented by a subset of neurons in the networkfiring synchronously. Because different representations are activated indifferent gamma cycles, the gamma rhythm serves to keep the individualmemories segmented in time. As reported by Jensen, the number of gammacycles per theta cycle determines the span of the working memory. FIG.7B illustrates a model accounting for theta phase precession in rats.Positional information is passed to the hippocampus, which activates therespective place cell representations and provokes the prospectiverecall of upcoming positions. In each theta cycle, time-compressedsequences are recalled at the rate of one representation per gammacycle.

FIG. 8A illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein. In FIG.8A, the nested stimulation waveform 802 includes multiple pulse bursts804 that are separated from one another by an inter-burst delay 808.Each of the pulse bursts 804 includes a series of individual pulses orspikes 810. The pulses 810 are delivered over a burst length 816 inconnection with an individual pulse bursts 804. The rate at which theindividual pulses 810 are delivered within a pulse bursts 804 isdetermined based on a pulse rate 812 (denoted as a bracket extendingbetween successive positive peaks of adjacent successive pulses 810).

FIG. 8A also illustrates a timeline extending along a horizontal axiswith various points in time noted along the nested stimulation waveform802. Each of the successive pulse bursts 804 are initiated at starttimes T10, T20 and T30, respectively. The interval between successivestart times (e.g. T10 and T-20) represents the burst to burst period814. The timeline also illustrates examples of the timing between pulses810 within an individual pulse burst (e.g. 804). For example, pulse peaktimes T1-T5 are illustrated as aligned with the peak positive point ofeach pulse 810. The pulse rate 812 corresponds to the pulse to pulseperiod 814.

The nested stimulation waveform may be decomposed into at least twoprimary waveform components, generally denoted as a carrier waveform 820and a high-frequency waveform 830. In accordance with embodimentsherein, the high frequency waveform is defined to correspond to highfrequency physiologic neural oscillations associated with the braintissue of interest, while the low frequency waveform is defined tocorrespond to low frequency physiologic neural oscillations associatedwith the brain tissue of interest. Optionally, one of the carrier andhigh frequency waveforms may be defined to differ from the low and highfrequency physiologic neural oscillations. For example, the highfrequency waveform may be defined to correspond to a physiologic beta orgamma wave, while the carrier waveform is defined to be independent of aphysiologic delta, theta or alpha wave. Alternatively, the highfrequency waveform may be defined to be independent of a physiologicbeta or gamma wave, while the carrier waveform is defined to correspondto a physiologic delta, theta or alpha wave.

The carrier wave 820 may represent a non-sinusoidal waveform similar toa square wave, but with only positive or only negative wave segments822. In the example of FIG. 8A, the carrier wave 820 includes a seriesof positive wave segments 822 that are defined by parameters, such as apredetermined amplitude 824, segment width 826, inter segment delay 828,among other parameters. The segment width 826 corresponds to the burstlength 816, while the inter segment delay 828 corresponds to theinterburst delay 808. The segment amplitude 824 defines an averageamplitude for each pulse burst 804.

The high-frequency waveform 830 includes a series of bursts 832. Withineach burst 832, the waveform 830 oscillates periodically by switchingbetween positive and negative amplitudes 834 and 835 at a selectfrequency 838. The high-frequency waveform 830 represents anintermittent waveform in that successive adjacent bursts 832 areseparated by an interburst delay 836 which corresponds to the interburstdelay 808 and inter segment delay 828. The high-frequency waveform 830is defined by various parameters such as the frequency 138, amplitudes834, 835, interburst delay 836.

The high-frequency waveform 830 is combined with the carrier waveform820 to form the nested stimulation waveform 802. The parameters of thehigh-frequency and carrier waveforms 830 and 820 may be adjusted toachieve various effects. As one example, the parameters may be adjustedto achieve cross frequency coupling with neural oscillations ofinterest. As one example, the parameters may be adjusted to entrainneural oscillations of interest. For example, the frequency, phase andamplitude of the carrier waveform 820 may be managed to entrain neuraloscillations associated with brain tissue of interest, such as tissueassociated with sensory, motor or cognitive processing. The carrierwaveform 820 may entrain neural oscillations to the temporal structuredefined by the carrier waveform 820 such as to facilitate selectiveattention in connection with certain psychiatric disorders (e.g.schizophrenia, dyslexia, attention deficit/hyperactivity disorder).Additionally or alternatively, the high-frequency waveform 830 may bemanaged to entrain neural oscillations associated with the brain regionof interest. For example, the frequency, phase, amplitude as well asother parameters may be adjusted for the high-frequency waveform 830 toobtain entrainment of the neural oscillations of interest.

The characteristics discussed herein in connection with FIG. 8Arepresent non-limiting examples of therapy parameters that may be variedto define different nested therapies (e.g., different carrier waveformsand different high frequency waveforms). For example, a nonlimiting listof potential therapy parameters include pulse amplitude, pulsefrequency, pulse to pulse period, the number of pulses in each burst,burst length, interburst delay, the number of pulse bursts in eachnested stimulation waveform and the like. The pulse bursts may includepulses having a frequency corresponding to high frequency intrinsicneural oscillations exhibited by normal/physiologic brain tissue ofinterest. The pulse bursts are separated from one another with a burstto burst period that corresponds to a frequency of the low-frequencyintrinsic neural oscillations exhibited by normal/physiologic braintissue of interest.

The nested stimulation waveform combines the carrier waveform and highfrequency waveform in a predetermined manner. For example, the carrierand high-frequency waveforms may be combined utilizing one of thefollowing types of cross frequency coupling: power to power; phase topower; phase to phase; phase to frequency; power to frequency andfrequency to frequency. Optionally, the carrier and high-frequencywaveforms are combined through phase to power cross frequency coupling,in which the phase of the carrier waveform modulates the power of thehigh-frequency waveform. For example, the waveforms 820 and 830 may becombined in the manners discussed herein in connection with FIGS. 4A-4G.

As one example, first parameters may be set to define the carrierwaveform to correspond to physiologic neural oscillations in the thetawave frequency band, while second parameters may be set to define thehigh-frequency waveform to correspond to physiologic neural oscillationsin the gamma wave frequency band. As explained herein, the nestedstimulation waveform may be defined to entrain and modulate the neuraloscillations in the gamma wave frequency band in connection with atleast one of sensory, motor, and cognitive events. Optionally, thenested stimulation waveform may be managed in connection with a patternof interest in neural oscillations through cross frequency couplingbetween theta and gamma waves associated with the brain tissue ofinterest.

As explained herein, the brain tissue of interest may correspond to onebrain region or comprise distributed neural modules located in separateregions of the brain. In accordance with embodiments herein methods andsystems may manage the nested stimulation waveform in connection withcross frequency coupling between neural oscillations associated with oneor distributed neural modules that exhibit long-distance communicationover neural oscillations within at least one of delta, theta and alphawave frequency bands.

In accordance with embodiments herein, methods and system measureintrinsic neural oscillations, determine whether the nested stimulationwaveform is achieving a desired modulation (e.g., entrainment) of theintrinsic neural oscillations, and adjust at least one of the first andsecond parameters to maintain the desired modulation (e.g., entrainment)of the intrinsic neural oscillations. The intrinsic neural oscillationsmay exhibit pathologic behavior or patterns. The nested stimulationwaveform is adjusted until the intrinsic neural oscillation exhibits aphysiologic behavior or pattern.

FIG. 8B illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein. In FIG.8B, the nested stimulation waveform 842 includes multiple pulse bursts844 that are separated from one another by an inter-burst delay 848.Each of the pulse burst 844 includes a series of individual pulses orspikes 850. The pulses 850 are delivered over a burst length 856 inconnection with an individual pulse burst 844. The rate at which theindividual pulses 850 are delivered within a pulse burst 844 isdetermined based on a pulse rate 862 (denoted as a bracket extendingbetween successive positive peaks of adjacent successive pulses 810. Thenested stimulation waveform 842 includes a low frequency carrierwaveform 853 and a high frequency waveform that defines thecharacteristics of the pulses 850.

FIG. 8C illustrates an alternative example of a nested stimulationwaveform that may be delivered in connection with nested therapies tobrain tissue (or brain tissue) of interest in accordance withembodiments herein. In FIG. 8C, the nested stimulation waveform 852includes multiple pulse bursts 854 that are separated from one anotherby an inter-burst delay 858. Each of the pulse burst 854 includes aseries of individual pulses or spikes 860. The pulses 810 are deliveredover a burst length 866 in connection with an individual pulse burst854. The rate at which the individual pulses 860 are delivered within apulse burst 854 is determined based on a pulse rate 862 (denoted as abracket extending between successive positive peaks of adjacentsuccessive pulses 860).

The nested stimulation waveform 852 is decomposed into a carrierwaveform 870 and a high-frequency waveform 880. The carrier wave 870 mayrepresent a sinusoidal waveform having positive and negative wavesegments 872. The positive and negative wave segments 822 are defined bya predetermined amplitude 874 and segment width 876 among otherparameters.

In some embodiments, the carrier wave 870 may exhibit an infraslowfrequency (less than 1 Hz, generally 0.001-1.0 Hz, and 0.01-0.1 Hz insome embodiments) as shown in, for example, FIG. 7C. In someembodiments, 0.01 Hz is employed for carrier wave 870 for electricalstimulation of one or more neuronal sites. Different infraslowfrequencies may be employed to integrate information from differentresting state networks depending upon the specific neurologicalcondition of the patient according to representative embodiments. Forexample, neurological disorders involving different parts of the ACC maybe treated by using an infraslow frequency of 0.02 Hz according toembodiments herein. Neurological disorders involving the PCC/precuneusmay be treated by using an infraslow frequency of 0.08 Hz according toembodiments herein. Neurological disorders involving the ACC andPCC/precuneus may be treated by using an infraslow frequency of0.09-0.11 Hz according to embodiments herein.

The high-frequency waveform 880 includes a series of bursts 882. Withineach burst 882, the waveform 880 oscillates periodically by switchingbetween positive and negative amplitudes 884 and 885 at a selectfrequency 888. The high-frequency waveform 880 represents anintermittent waveform in that successive adjacent bursts 882 areseparated by an interburst delay 886 which corresponds to the interburstdelay 858.

The high-frequency waveform 880 is combined with the carrier waveform870 to form the nested stimulation waveform 852. The parameters of thehigh-frequency and carrier waveforms 880 and 870 are adjusted to entrainand/or achieve cross frequency coupling with neural oscillations ofinterest. For example, the frequency, phase and amplitude of the carrierwaveform 870 may be managed to entrain neural oscillations associatedwith a brain region of interest, such as a brain region associated withsensory, motor or cognitive processing. The carrier waveform 870 mayentrain neural oscillations to the temporal structure defined by thecarrier waveform 870 such as to facilitate selective attention inconnection with certain psychiatric disorders (e.g. schizophrenia,dyslexia, attention deficit/hyperactivity disorder). Additionally oralternatively, the high-frequency waveform 880 may be managed to entrainneural oscillations associated with the brain region of interest. Forexample, the frequency, phase, amplitude as well as other parameters maybe adjusted for the high-frequency waveform 880 to obtain entrainment ofthe neural oscillations of interest.

The carrier and high-frequency waveforms 870 and 880 may be combinedutilizing one of the following types of cross frequency coupling: powerto power; phase to power; phase to phase; phase to frequency; power tofrequency and frequency to frequency. For example, the waveforms 870 and880 may be combined in the manner discussed herein in connection withFIGS. 4A-4G. As one example, the carrier and high-frequency waveforms870 and 880 are combined through phase to power cross frequency coupling(as illustrated in connection with the waveform 405 in FIGS. 4A-4G), inwhich the phase of the carrier waveform modulates the power of thehigh-frequency waveform.

FIGS. 9A-9F illustrate alternative nested stimulation waveforms that maybe utilized in accordance with embodiments herein. The nestedstimulation waveforms 902-912 may be delivered from multiple electrodecombinations along the lead. The nested stimulation waveform 902includes a carrier waveform that is cross frequency coupled to a highfrequency waveform to form multiple (e.g. three) pulse bursts 922separated by an inter-burst interval 924. The pulse burst 922 include aseries of pulses 926 having a common polarity (e.g. all positive pulsesor all negative pulses).

The nested stimulation waveform 904 includes a pair of pulse bursts 932separated by an interburst interval 934. Each pulse burst 932 includes aseries of pulses 936 (e.g. three) that have a common polarity. Thenested stimulation waveform 906 includes a single pulse burst 942 havinga series of pulses 946, each of which is bipolar (e.g. extends betweenpositive and negative polarities). The pulses 946 have one of twostates/voltage levels, namely a positive pulse amplitude and a negativepulse amplitude that are common.

The stimulation waveform 908 includes a pair of pulse bursts 952separated by an inter-burst interval 954. Each pulse burst 952 includesmultiple pulses 956 that are bipolar (extending between positive andnegative polarities). The pulses 956 vary between more than two statesor voltage levels, namely first and second positive voltages 957-958 andfirst and second negative voltages 959 and 960. Optionally, additionalvoltage levels/states may be utilized and the positive and negativevoltage levels need not be common.

The nested stimulation waveform 910 includes pulse burst 962A-962D thatare separated by an interburst interval 964. The interburst intervals964 may differ from one another or be common. The pulse bursts 962A and962C have similar positive and negative amplitudes, while the pulsebursts 962B (positive) and 962D (negative) are monopolar and differentfrom one another. The nested stimulation waveform 912 illustrates asingle pulse burst 972 that has a carrier wave component (as denoted byenvelope 973 in dashed lines) that is modulated by a higher frequencycomponent (as denoted by solid lines 975). Optionally, the nestedstimulation waveform may be varied from the foregoing examples.Additionally, separate and distinct nested stimulation waveforms may bedelivered from different electrode combinations at non-overlappingdistinct points in time.

Electrical Stimulation Devices

FIGS. 1A-1B illustrate example neurological stimulation (NS) systems 10for electrically stimulating a predetermined site area to treat one ormore neurological disorders or conditions. In general terms, stimulationsystem 10 includes an implantable pulse generating source or electricalIMD 12 (generally referred to as an “implantable medical device” or“IMD”) and one or more implantable electrodes or electrical stimulationleads 14 for applying nested stimulation pulses to a predetermined site.In operation, both of these primary components are implanted in theperson's body, as discussed below. In certain embodiments, IMD 12 iscoupled directly to a connecting portion 16 of stimulation lead 14. Insome embodiments, IMD 12 is incorporated into the stimulation lead 14and IMD 12 instead is embedded within stimulation lead 14. For example,such a stimulation system 10 may be a Bion.RTM. stimulation systemmanufactured by Advanced Bionics Corporation. Whether IMD 12 is coupleddirectly to or embedded within the stimulation lead 14, IMD 12 controlsthe stimulation pulses transmitted to one or more stimulation electrodes18 located on a stimulating portion 20 of stimulation lead 14,positioned in communication with a predetermined site, according tosuitable therapy parameters (e.g., duration, amplitude or intensity,frequency, pulse width, firing delay, etc.).

As contemplated in embodiments herein, a predetermined stimulation sitefor tissue of interest can include either peripheral neuronal tissueand/or central neuronal tissue. Neuronal tissue includes any tissueassociated with the peripheral nervous system or the central nervoussystem. Peripheral neuronal tissue can include a nerve root or rootganglion or any neuronal tissue that lies outside the brain, brainstemor spinal cord. Peripheral nerves can include, but are not limited toolfactory nerve, optic, nerve, oculomotor nerve, trochlear nerve,trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear(auditory) nerve, glossopharyngeal nerve, vagal nerve, accessory nerve,hypoglossal nerve, suboccipital nerve, the greater occipital nerve, thelesser occipital nerve, the greater auricular nerve, the lesserauricular nerve, the phrenic nerve, brachial plexus, radial axillarynerves, musculocutaneous nerves, radial nerves, ulnar nerves, mediannerves, intercostal nerves, lumbosacral plexus, sciatic nerves, commonperoneal nerve, tibial nerves, sural nerves, femoral nerves, glutealnerves, thoracic spinal nerves, obturator nerves, digital nerves,pudendal nerves, plantar nerves, saphenous nerves, ilioinguinal nerves,gentofemoral nerves, and iliohypogastric nerves.

Central neuronal tissue includes brain tissue, spinal tissue orbrainstem tissue. Brain tissue can include thalamus/sub-thalamus, basalganglia, hippocampus, amygdala, hypothalamus, mammilary bodies,substantia nigra or cortex or white matter tracts afferent to orefferent from the abovementioned brain tissue, inclusive of the corpuscallosum. Spinal tissue can include the ascending and descending tractsof the spinal cord, more specifically, the ascending tracts of thatcomprise intralaminar neurons or the dorsal column. The brainstem tissuecan include the medulla oblongata, pons or mesencephalon, moreparticular the posterior pons or posterior mesencephalon, Lushka'sforamen, and ventrolateral part of the medulla oblongata.

A doctor, the patient, or another user of IMD 12 may directly or indirectly input therapy parameters to specify or modify the nature of thestimulation provided.

In FIG. 1B, the IMD 12 includes an implantable wireless receiver. Anexample of a wireless receiver may be one manufactured by AdvancedNeuromodulation Systems, Inc., such as the Renew™ System, part numbers3408 and 3416. In another embodiment, the IMD can be optimized for highfrequency operation as described in U.S. Provisional Application Ser.No. 60/685,036, filed May 26, 2005, entitled “SYSTEMS AND METHODS FORUSE IN PULSE GENERATION,” which is incorporated herein by reference. Thewireless receiver is capable of receiving wireless signals from awireless transmitter 22 located external to the person's body. Thewireless signals are represented in FIG. 1B by wireless link symbol 24.A doctor, the patient, or another user of IMD 12 may use a controller 26located external to the person's body to provide control signals foroperation of IMD 12. Controller 26 provides the control signals towireless transmitter 22, wireless transmitter 22 transmits the controlsignals and power to the wireless receiver of IMD 12, and IMD 12 usesthe control signals to vary the signal parameters of electrical signalstransmitted through electrical stimulation lead 14 to the stimulationsite. Thus, the external controller 26 can be for example, a handheldprogrammer, to provide a means for programming the IMD. An examplewireless transmitter may be one manufactured by Advanced NeuromodulationSystems, Inc., such as the Renew™ System, part numbers 3508 and 3516.

The IMD 12 applies burst stimulation to brain tissue of a patient.Specifically, the IMD includes a microprocessor and a pulse generationmodule. The pulse generation module generates the electrical pulsesaccording to a defined pulse width and pulse amplitude and applies theelectrical pulses to defined electrodes. The microprocessor controls theoperations of the pulse generation module according to softwareinstructions stored in the device.

The IMD 12 can be adapted by programming the microprocessor to deliver anumber of spikes (relatively short pulse width pulses) that areseparated by an appropriate interspike interval. Thereafter, theprogramming of the microprocessor causes the pulse generation module tocease pulse generation operations for an interburst interval. Theprogramming of the microprocessor also causes a repetition of the spikegeneration and cessation of operations for a predetermined number oftimes. After the predetermined number of repetitions has been completedwithin a nested stimulation waveform, the microprocessor can cause burststimulation to cease for an amount of time (and resume thereafter).Also, in some embodiments, the microprocessor could be programmed tocause the pulse generation module to deliver a hyperpolarizing pulsebefore the first spike of each group of multiple spikes.

The microprocessor can be programmed to allow the variouscharacteristics of the burst stimulus to be set by a physician to allowthe burst stimulus to be optimized for a particular pathology of apatient. For example, the spike amplitude, the interspike interval, theinterburst interval, the number of bursts to be repeated in succession,the electrode combinations, the firing delay between nested stimulationwaveforms delivered to different electrode combinations, the amplitudeof the hyperpolarizing pulse, and other such characteristics could becontrolled using respective parameters accessed by the microprocessorduring burst stimulus operations. These parameters could be set todesired values by an external programming device via wirelesscommunication with the implantable neuromodulation device.

In representative embodiments, IMD 12 applies electrical stimulationaccording to a suitable noise signal (white noise, pink noise, brownnoise, etc.). Details regarding implementation of a suitable noisesignal can be found in U.S. Pat. No. 8,682,441, which is incorporatedherein by reference

In another embodiment, the IMD 12 can be implemented to apply burststimulation using a digital signal processor and one or severaldigital-to-analog converters. The burst stimulus waveform could bedefined in memory and applied to the digital-to-analog converter(s) forapplication through electrodes of the medical lead. The digital signalprocessor could scale the various portions of the waveform in amplitudeand within the time domain (e.g., for the various intervals) accordingto the various burst parameters.

FIG. 1C depicts an NS system 100 that delivers stimulation therapies inaccordance with embodiments herein. For example, the NS system 100 maybe adapted to stimulate spinal cord tissue, peripheral nervous tissue,deep brain tissue, or any other suitable nervous/brain tissue ofinterest within a patient's body.

The NS system 100 may be controlled to deliver various types of nestedstimulation therapy, such as high frequency neurostimulation therapies,burst neurostimulation therapies and the like. High frequencyneurostimulation includes a continuous series of monophasic or biphasicpulses that are delivered at a predetermined frequency. Burstneurostimulation includes short sequences of monophasic or biphasicpulses, where each sequence is separated by a quiescent period. Ingeneral, nested therapies include a continuous, repeating orintermittent pulse sequence delivered at a frequency and amplitudeconfigured to avoid inducing (or introduce a very limited) paresthesia.

The NS system 100 may deliver nested stimulation therapy based onpreprogrammed therapy parameters. The therapy parameters may include,among other things, pulse amplitude, pulse polarity, pulse width, pulsefrequency, interpulse interval, inter burst interval, electrodecombinations, firing delay and the like. Optionally, the NS system 100may represent a closed loop neurostimulation device that is configuredto provide real-time sensing functions from a lead. The configuration ofthe lead sensing electrodes may be varied depending on the neuronalanatomy of the sensing site(s) of interest. The size and shape ofelectrodes is varied based on the implant location. The electroniccomponents within the NS system 100 are designed with both stimulationand sensing capabilities, including alternative nested stimulationtherapy, such as burst mode, high frequency mode and the like.

The NS system 100 includes an implantable medical device (IMD) 150 thatis adapted to generate electrical pulses for application to tissue of apatient. The IMD 150 typically comprises a metallic housing or can 158that encloses a controller 151, pulse generating circuitry 152, a chargestorage circuit 153, a battery 154, a far-field and/or near fieldcommunication circuitry 155, battery charging circuitry 156, switchingcircuitry 157, memory 158 and the like. The charge storage circuit 153may represent one or more capacitors and/or battery cells that storecharge used to produce the therapies described herein. The pulsegenerating circuitry 152, under control of the controller 151, managesdischarge of the charge storage circuit 153 to shape the morphology ofthe waveform delivered while discharging energy. The switching circuitry157 connects select combinations of the electrodes 121 a-d to the pulsegenerating circuitry 152 thereby directing the stimulation waveform to adesired electrode combination. As explained herein, the switchingcircuitry 157 successively connects the pulse generating circuitry 152to successive electrode combinations 123 and 125. The components 151-158are also within the IMD 12 (FIGS. 1A and 1B).

The controller 151 typically includes one or more processors, such as amicrocontroller, for controlling the various other components of thedevice. Software code is typically stored in memory of the IMD 150 forexecution by the microcontroller or processor to control the variouscomponents of the device.

The IMD 150 may comprise a separate or an attached extension component170. If the extension component 170 is a separate component, theextension component 170 may connect with the “header” portion of the IMD150 as is known in the art. If the extension component 170 is integratedwith the IMD 150, internal electrical connections may be made throughrespective conductive components. Within the IMD 150, electrical pulsesare generated by the pulse generating circuitry 152 and are provided tothe switching circuitry 157. The switching circuitry 157 connects tooutputs of the IMD 150. Electrical connectors (e.g., “Bal-Seal”connectors) within the connector portion 171 of the extension component170 or within the IMD header may be employed to conduct variousstimulation pulses. The terminals of one or more leads 110 are insertedwithin connector portion 171 or within the IMD header for electricalconnection with respective connectors. Thereby, the pulses originatingfrom the IMD 150 are provided to the lead 110. The pulses are thenconducted through the conductors of the lead 110 and applied to tissueof a patient via stimulation electrodes 121 a-d that are coupled toblocking capacitors. Any suitable known or later developed design may beemployed for connector portion 171.

The stimulation electrodes 121 a-d may be positioned along a horizontalaxis 102 of the lead 110, and are angularly positioned about thehorizontal axis 102 so the stimulation electrodes 121 a-d do notoverlap. The stimulation electrodes 121 a-d may be in the shape of aring such that each stimulation electrode 121 a-d continuously coversthe circumference of the exterior surface of the lead 110. Adjacentstimulation electrodes 121 a-d are separated from one another bynon-conducting rings 112, which electrically isolate each stimulationelectrode 121 a-d from an adjacent stimulation electrode 121 a-d. Thenon-conducting rings 112 may include one or more insulative materialsand/or biocompatible materials to allow the lead 110 to be implantablewithin the patient. Non-limiting examples of such materials includepolyimide, polyetheretherketone (PEEK), polyethylene terephthalate (PET)film (also known as polyester or Mylar), polytetrafluoroethylene (PTFE)(e.g., Teflon), or parylene coating, polyether bloc amides,polyurethane. The stimulation electrodes 121 a-d may be configured toemit the pulses in an outward radial direction proximate to or within astimulation target. Additionally or alternatively, the stimulationelectrodes 121 a-d may be in the shape of a split or non-continuous ringsuch that the pulse may be directed in an outward radial directionadjacent to the stimulation electrodes 121 a-d. The stimulationelectrodes 121 a-d deliver tonic, high frequency and/or burst nestedstimulation waveforms as described herein. Optionally, the electrodes121 a-d may also sense neural oscillations and/or sensory actionpotential (neural oscillation signals) for a data collection window.

The lead 110 may comprise a lead body 172 of insulative material about aplurality of conductors within the material that extend from a proximalend of lead 110, proximate to the IMD 150, to its distal end. Theconductors electrically couple a plurality of the stimulation electrodes121 to a plurality of terminals (not shown) of the lead 110. Theterminals are adapted to receive electrical pulses and the stimulationelectrodes 121 a-d are adapted to apply the pulses to the stimulationtarget of the patient. Also, sensing of physiological signals may occurthrough the stimulation electrodes 121 a-d, the conductors, and theterminals. It should be noted that although the lead 110 is depictedwith four stimulation electrodes 121 a-d, the lead 110 may include anysuitable number of stimulation electrodes 121 a-d (e.g., less than four,more than four) as well as terminals, and internal conductors.Additionally or alternatively, various sensors (e.g., a positiondetector, a radiopaque fiducial) may be located near the distal end ofthe lead 110 and electrically coupled to terminals through conductorswithin the lead body 172.

Although not required for any embodiments, the lead body 172 of the lead110 may be fabricated to flex and elongate upon implantation oradvancing within the tissue (e.g., nervous tissue) of the patienttowards the stimulation target and movements of the patient during orafter implantation. By fabricating the lead body 172, according to someembodiments, the lead body 172 or a portion thereof is capable ofelastic elongation under relatively low stretching forces. Also, afterremoval of the stretching force, the lead body 172 may be capable ofresuming its original length and profile.

By way of example, the IMD 12, 150 may include a processor andassociated charge control circuitry as described in U.S. Pat. No.7,571,007, entitled “SYSTEMS AND METHODS FOR USE IN PULSE GENERATION,”which is expressly incorporated herein by reference. Circuitry forrecharging a rechargeable battery (e.g., battery charging circuitry 156)of an IMD using inductive coupling and external charging circuits aredescribed in U.S. Pat. No. 7,212,110, entitled “IMPLANTABLE DEVICE ANDSYSTEM FOR WIRELESS COMMUNICATION,” which is expressly incorporatedherein by reference. An example and discussion of “constant current”pulse generating circuitry (e.g., pulse generating circuitry 152) isprovided in U.S. Patent Publication No. 2006/0170486 entitled “PULSEGENERATOR HAVING AN EFFICIENT FRACTIONAL VOLTAGE CONVERTER AND METHOD OFUSE,” which is expressly incorporated herein by reference. One ormultiple sets of such circuitry may be provided within the IMD 12, 150.Different burst and/or high frequency pulses on different stimulationelectrodes may be generated using a single set of the pulse generatingcircuitry using consecutively generated pulses according to a“multi-stimset program” as is known in the art. Complex pulse parametersmay be employed such as those described in U.S. Pat. No. 7,228,179,entitled “Method and apparatus for providing complex tissue stimulationpatterns,” and International Patent Publication Number WO 2001/093953A1, entitled “NEUROMODULATION THERAPY SYSTEM,” which are expresslyincorporated herein by reference. Alternatively, multiple sets of suchcircuitry may be employed to provide pulse patterns (e.g., tonicstimulation waveform, burst stimulation waveform) that include generatedand delivered stimulation pulses through various stimulation electrodesof one or more leads as is also known in the art. Various sets ofparameters may define the pulse characteristics and pulse timing for thepulses applied to the various stimulation electrodes. Although constantcurrent pulse generating circuitry is contemplated for some embodiments,any other suitable type of pulse generating circuitry may be employedsuch as constant voltage pulse generating circuitry.

The controller 151 delivers a nested stimulation waveform to at leastone electrode combination located proximate to nervous tissue ofinterest, the nested stimulation waveform including a series of pulsesconfigured to excite the nested C-fibers of the nervous tissue ofinterest, the nested stimulation waveform defined by therapy parameters.The controller 151 may deliver the nested stimulation waveform based onpreprogrammed therapy parameters. The preprogrammed therapy parametersmay be set based on information collected from numerous past patientsand/or test performed upon an individual patient during initial implantand/or during periodic checkups.

Optionally, the controller 151 senses intrinsic neural oscillations fromat least one electrode on the lead. Optionally, the controller 151analyzes the intrinsic neural oscillations signals to obtain brainactivity data. The controller 151 determines whether the activity datasatisfies a criteria of interest. The controller 151 adjusts at leastone of the therapy parameters to change the nested stimulation waveformwhen the activity data does not satisfy the criteria of interest. Thecontroller 151 iteratively repeats the delivering operations for a groupof TPS. The IMD selects a candidate TPS from the group of TPS based on acriteria of interest. The therapy parameters define at least one of aburst stimulation waveform or a high frequency stimulation waveform. Thecontroller 151 may repeat the delivering, sensing and adjustingoperations to optimize the nested stimulation waveform. The analyzingoperation may include analyzing a feature of interest from a morphologyof the neural oscillation signal over time, counting a number ofoccurrences of the feature of interest that occur within the signal overa predetermined duration, and generating the activity data based on thenumber of occurrences of the feature of interest.

Memory 158 stores software to control operation of the controller 151for nested stimulation therapy as explained herein. The memory 158 alsostores neural oscillation signals, therapy parameters, neuraloscillation activity level data, sensation scales and the like. Forexample, the memory 158 may save neural oscillation activity level datafor various different therapies as applied over a short or extendedperiod of time. A collection of neural oscillation activity level datais accumulated for different therapies and may be compared to identifyhigh, low and acceptable amounts of sensory activity.

A controller device 160 may be implemented to charge/recharge thebattery 154 of the IMD 150 (although a separate recharging device couldalternatively be employed) and to program the IMD 150 on the pulsespecifications while implanted within the patient. Although, inalternative embodiments separate programmer devices may be employed forcharging and/or programming the NS system 100. The controller device 160may be a processor-based system that possesses wireless communicationcapabilities. Software may be stored within a non-transitory memory ofthe controller device 160, which may be executed by the processor tocontrol the various operations of the controller device 160. A “wand”165 may be electrically connected to the controller device 160 throughsuitable electrical connectors (not shown). The electrical connectorsmay be electrically connected to a telemetry component 166 (e.g.,inductor coil, RF transceiver) at the distal end of wand 165 throughrespective wires (not shown) allowing bi-directional communication withthe IMD 150. Optionally, in some embodiments, the wand 165 may compriseone or more temperature sensors for use during charging operations.

The user may initiate communication with the IMD 150 by placing the wand165 proximate to the NS system 100. Preferably, the placement of thewand 165 allows the telemetry system of the wand 165 to be aligned withthe far-field and/or near field communication circuitry 155 of the IMD150. The controller device 160 preferably provides one or more userinterfaces 168 (e.g., touchscreen, keyboard, mouse, buttons, or thelike) allowing the user to operate the IMD 150. The controller device160 may be controlled by the user (e.g., doctor, clinician) through theuser interface 168 allowing the user to interact with the IMD 150. Theuser interface 168 may permit the user to move electrical stimulationalong and/or across one or more of the lead(s) 110 using differentstimulation electrode 121 combinations, for example, as described inU.S. Patent Application Publication No. 2009/0326608, entitled “METHODOF ELECTRICALLY STIMULATING TISSUE OF A PATIENT BY SHIFTING A LOCUS OFSTIMULATION AND SYSTEM EMPLOYING THE SAME,” which is expresslyincorporated herein by reference.

Also, the controller device 160 may permit operation of the IMD 12, 150according to one or more therapies to treat the patient. Each therapymay include one or more sets of stimulation parameters of the pulseincluding pulse amplitude, pulse width, pulse frequency or inter-pulseperiod, firing delay, pulse repetition parameter (e.g., number of timesfor a given pulse to be repeated for respective stimset during executionof program), biphasic pulses, monophasic pulses, etc. The IMD 150modifies its internal parameters in response to the control signals fromthe controller device 160 to vary the stimulation characteristics of thestimulation pulses transmitted through the lead 110 to the tissue of thepatient. NS systems, stimsets, and multi-stimset programs are discussedin PCT Publication No. WO 01/93953, entitled “NEUROMODULATION THERAPYSYSTEM,” and U.S. Pat. No. 7,228,179, entitled “METHOD AND APPARATUS FORPROVIDING COMPLEX TISSUE STIMULATION PATTERNS,” which are expresslyincorporated herein by reference.

FIGS. 2A-2I illustrate example stimulation leads 14 that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions. As described above, each of theone or more stimulation leads 14 incorporated in stimulation systems 10,100 includes one or more stimulation electrodes 18 adapted to bepositioned in communication with the predetermined site and used todeliver the stimulation pulses received from IMD 12 (or pulse generatingcircuitry 157 in FIG. 1C). A percutaneous stimulation lead 14(corresponding to the lead 110 in FIG. 1C), such as example stimulationleads 14 a-d, includes one or more circumferential electrodes 18 spacedapart from one another along the length of stimulating portion 20 ofstimulation lead 14. Circumferential electrodes 18 emit electricalstimulation energy generally radially (e.g., generally perpendicular tothe axis of stimulation lead 14) in all directions. A laminotomy,paddle, or surgical stimulation lead 14, such as example stimulationleads 14e-i, includes one or more directional stimulation electrodes 18spaced apart from one another along one surface of stimulation lead 14.Directional stimulation electrodes 18 emit electrical stimulation energyin a direction generally perpendicular to the surface of stimulationlead 14 on which they are located. Although various types of stimulationleads 14 are shown as examples, embodiments herein contemplatestimulation system 10 including any suitable type of stimulation lead 14in any suitable number. In addition, stimulation leads 14 may be usedalone or in combination. For example, medial or unilateral stimulationof the predetermined site may be accomplished using a single electricalstimulation lead 14 implanted in communication with the predeterminedsite in one side of the head, while bilateral electrical stimulation ofthe predetermined site may be accomplished using two stimulation leads14 implanted in communication with the predetermined site in oppositesides of the head.

In one embodiment, the stimulation source is transcutaneously incommunication with the electrical stimulation lead. In “transcutaneous”electrical nerve stimulation (TENS), the stimulation source is externalto the patient's body, and may be worn in an appropriate fanny pack orbelt, and the electrical stimulation lead is in communication with thestimulation source, either remotely or directly. In another embodiment,the stimulation is percutaneous. In “percutaneous” electrical nervestimulation (PENS), needles are inserted to an appropriate depth aroundor immediately adjacent to a predetermined stimulation site, and thenstimulated.

The IMD 12, 150 allow each electrode of each lead to be defined as apositive, a negative, or a neutral polarity. For each electrodecombination (e.g., the defined polarity of at least two electrodeshaving at least one cathode and at least one anode), an electricalsignal can have at least a definable amplitude (e.g., voltage), pulsewidth, and frequency, where these variables may be independentlyadjusted to finely select the sensory transmitting brain tissue requiredto inhibit transmission of neuronal signals. Generally, amplitudes,pulse widths, and frequencies are determinable by the capabilities ofthe neurostimulation systems, which are known by those of skill in theart. Voltages that may be used can include, for example about 0.5 toabout 10 volts, more preferably about 1 to about 10 volts.

In embodiments herein, the therapy parameter of signal frequency isvaried to achieve a burst type rhythm, or burst mode stimulation.Generally, the burst stimulus frequency may be in the range of about0.01 Hz to about 100 Hz, more particular, in the range of about 1 Hz toabout 12 Hz, and more particularly, in the range of about 1 Hz to about4 Hz, 4 Hz to about 7 Hz or about 8 Hz to about 12 Hz for each burst.Each burst stimulus comprises at least two spikes, for example, eachburst stimulus can comprise about 2 to about 100 spikes, moreparticularly, about 2 to about 10 spikes. Each spike can comprise afrequency in the range of about 50 Hz to about 1000 Hz, moreparticularly, in the range of about 200 Hz to about 500 Hz. Thefrequency for each spike within a burst can be variable, thus it is notnecessary for each spike to contain similar frequencies, e.g., thefrequencies can vary in each spike. The inter-spike interval can be alsovary, for example, the inter-spike interval, can be about 0.1milliseconds to about 100 milliseconds or any range there between.

The burst stimulus is followed by an inter-burst interval, during whichsubstantially no stimulus is applied. The inter-burst interval hasduration in the range of about 1 milliseconds to about 5 seconds, morepreferably, 10 milliseconds to about 300 milliseconds. It is envisionedthat the burst stimulus has a duration in the range of about 1milliseconds to about 5 seconds, more particular, in the range of about250 msec to 1000 msec (1-4 Hz burst firing), 145 msec to about 250 msec(4-7 Hz,), 145 msec to about 80 msec (8-12 Hz) or 1 to 5 seconds inplateau potential firing. The burst stimulus and the inter-burstinterval can have a regular pattern or an irregular pattern (e.g.,random or irregular harmonics). More specifically, the burst stimuluscan have a physiological pattern or a pathological pattern. Additionaldetails regarding burst stimulation may be found in U.S. Pat. No.8,897,870, which is incorporated herein by reference.

It is envisaged that the patient will require intermittent assessmentwith regard to patterns of stimulation. Different electrodes on the leadcan be selected by suitable computer programming, such as that describedin U.S. Pat. No. 5,938,690, which is incorporated by reference here infull. Utilizing such a program allows an optimal stimulation pattern tobe obtained at minimal voltages. This ensures a longer battery life forthe implanted systems.

FIGS. 2A-2I respectively depict stimulation portions for inclusion atthe distal end of lead. Stimulation portion depicts a conventionalstimulation portion of a “percutaneous” lead with multiple ringelectrodes. Stimulation portion depicts a stimulation portion includingseveral segmented electrodes. Example fabrication processes aredisclosed in U.S. patent application Ser. No. 12/895,096, entitled,“METHOD OF FABRICATING STIMULATION LEAD FOR APPLYING ELECTRICALSTIMULATION TO TISSUE OF A PATIENT,” which is incorporated herein byreference. Stimulation portion includes multiple planar electrodes on apaddle structure.

A. Deep Brain Stimulation

In certain embodiments, for example, patients may have an electricalstimulation lead or electrode implanted into the brain. The anatomicaltargets or predetermined site may be stimulated directly or affectedthrough stimulation in another region of the brain.

In embodiments herein, the predetermined site or implant sites include,but are not limited to thalamus/sub-thalamus, basal ganglia,hippocampus, amygdala, hypothalamus, mammilary bodies, substantia nigraor cortex or white matter tracts afferent to or efferent from theabovementioned brain tissue, inclusive of the corpus callosum. Stillfurther, the predetermined site may comprise the auditory cortex and/orsomatosensory cortex in which the stimulation devices is implantedcortically.

Once electrical stimulation lead 14, 110 has been positioned in thebrain, lead 14, 110 is uncoupled from any stereotactic equipmentpresent, and the cannula and stereotactic equipment are removed. Wherestereotactic equipment is used, the cannula may be removed before,during, or after removal of the stereotactic equipment. Connectingportion 16 of electrical stimulation lead 14, 110 is laid substantiallyflat along the skull. Where appropriate, any burr hole cover seated inthe burr hole may be used to secure electrical stimulation lead 14, 110in position and possibly to help prevent leakage from the burr hole andentry of contaminants into the burr hole.

Once electrical stimulation lead 14, 110 has been inserted and secured,connecting portion of lead 14, 110 extends from the lead insertion siteto the implant site at which IMD 12, 150 is implanted. The implant siteis typically a subcutaneous pocket formed to receive and house IMD 12,150. The implant site is usually positioned a distance away from theinsertion site, such as near the chest, below the clavicle oralternatively near the buttocks or another place in the torso area. Onceall appropriate components of stimulation system 10, 100 are implanted,these components may be subject to mechanical forces and movement inresponse to movement of the person's body. A doctor, the patient, oranother user of IMD 12, 150 may directly or in directly input signalparameters for controlling the nature of the electrical stimulationprovided.

Although example steps are illustrated and described, embodiments hereincontemplate two or more steps taking place substantially simultaneouslyor in a different order. In addition, embodiments herein contemplateusing methods with additional steps, fewer steps, or different steps, solong as the steps remain appropriate for implanting an examplestimulation system 10, 100 into a person for electrical stimulation ofthe person's brain.

Brainstem Stimulation

The stimulation system 10, 100, described above, can be implanted into aperson's body with stimulation lead 14 located in communication with apredetermined brainstem tissue and/or area. Such systems that can beused are described in WO2004062470, which is incorporated herein byreference in its entirety.

The predetermined brainstem tissue can be selected from medullaoblongata, pons or mesencephalon, more particular the posterior pons orposterior mesencephalon, Luschka's or Magendie's foramen, andventrolateral part of the medulla oblongata.

Implantation of a stimulation lead 14 in communication with thepredetermined brainstem area can be accomplished via a variety ofsurgical techniques that are well known to those of skill in the art.For example, an electrical stimulation lead can be implanted on, in, ornear the brainstem by accessing the brain tissue through a percutaneousroute, an open craniotomy, or a burr hole. Where a burr hole is themeans of accessing the brainstem, for example, stereotactic equipmentsuitable to aid in placement of an electrical stimulation lead 14 on,in, or near the brainstem may be positioned around the head. Anotheralternative technique can include, a modified midline or retrosigmoidposterior fossa technique.

In certain embodiments, electrical stimulation lead 14 is located atleast partially within or below the gray or white matter of thebrainstem. Alternatively, a stimulation lead 14 can be placed incommunication with the predetermined brainstem area by threading thestimulation lead up the spinal cord column, as described above, which isincorporated herein.

As described above, each of the one or more leads 14 incorporated instimulation system 10 includes one or more electrodes 18 adapted to bepositioned near the target brain tissue and used to deliver electricalstimulation energy to the target brain tissue in response to electricalsignals received from IMD 12. A percutaneous lead 14 may include one ormore circumferential electrodes 18 spaced apart from one another alongthe length of lead 14. Circumferential electrodes 18 emit electricalstimulation energy generally radially in all directions and may beinserted percutaneously or through a needle. The electrodes 18 of apercutaneous lead 14 may be arranged in configurations other thancircumferentially, for example as in a “coated” lead 14. A laminotomy orpaddle style lead 14, such as example leads 14e-i, includes one or moredirectional electrodes 18 spaced apart from one another along onesurface of lead 14. Directional electrodes 18 emit electricalstimulation energy in a direction generally perpendicular to the surfaceof lead 14 on which they are located. Although various types of leads 14are shown as examples, embodiments herein contemplate stimulation system10 including any suitable type of lead 14 in any suitable number,including three-dimensional leads and matrix leads as described below.In addition, the leads may be used alone or in combination.

Yet further, a stimulation lead 14 can be implanted in communicationwith the predetermined brainstem area by a using stereotactic proceduressimilar to those described above, which are incorporated herein, forimplantation via the cerebrum.

Still further, a predetermined brainstem area can be in directlystimulated by implanting a stimulation lead 14 in communication with acranial nerve (e.g., olfactory nerve, optic, nerve, oculomoter nerve,trochlear nerve, trigeminal nerve, abducent nerve, facial nerve,vestibulocochlear nerve, glossopharyngeal nerve, vagal nerve, accessorynerve, and the hypoglossal nerve) as well as high cervical nerves(cervical nerves have anastomoses with lower cranial nerves) such thatstimulation of a cranial nerve in directly stimulates the predeterminedbrainstem tissue. Such techniques are further described in U.S. Pat.Nos. 6,721,603; 6,622,047; and 5,335,657, and U.S. ProvisionalApplication 60/591,195 entitled “Stimulation System and Method forTreating a Neurological Disorder” each of which are incorporated hereinby reference.

Although example steps are illustrated and described, embodiments hereincontemplate two or more steps taking place substantially simultaneouslyor in a different order. In addition, embodiments herein contemplateusing methods with additional steps, fewer steps, or different steps, solong as the steps remain appropriate for implanting stimulation system10 into a person for electrical stimulation of the predetermined site.

In the auditory system, tonic firing transmits the contents of auditoryinformation, while burst firing transmit the valence or importanceattached to that sound (Lisman 1997; Sherman 2001; Swadlow and Gusev2001). Repetitive stimulus presentation results in decreased neuronalresponse to that stimulus, known as auditory habituation at the singlecell level (Ulanovsky et al., 2003), auditory mismatch negativity atmultiple cell level (Naatanen et al., 1993; Ulanovsky et al., 2003).

Tinnitus is a noise in the ears, often described as ringing, buzzing,roaring, or clicking Subjective and objective forms of tinnitus exist,with objective tinnitus often caused by muscle contractions or otherinternal noise sources in the area proximal to auditory structures. Incertain cases, external observers can hear the sound generated by theinternal source of objective tinnitus. In subjective forms, tinnitus isaudible only to the subject. Tinnitus varies in perceived amplitude,with some subjects reporting barely audible forms and others essentiallydeaf to external sounds and/or incapacitated by the intensity of theperceived noise.

Tinnitus is usually constantly present, e.g., a non-rational valence isattached to the internally generated sound, and there is no auditoryhabituation to this specific sound, at this specific frequency. Thus,tinnitus is the result of hyperactivity of lesion-edge frequencies, andauditory mismatch negativity in tinnitus patients is specific forfrequencies located at the audiometrically normal lesion edge (Weisz2004).

As pathological valence of the tinnitus sound is mediated by burstfiring, burst firing is increased in tinnitus in the extralemniscalsystem (Chen and Jastreboff 1995; Eggermont and Kenmochi 1998; Eggermont2003), in the inner hair cells (Puel 1995; Puel et al., 2002), theauditory nerve (Moller 1984), the dorsal and external inferiorcolliculus (Chen and Jastreboff 1995), the thalamus (Jeanmonod, Magninet al., 1996) and the secondary auditory cortex (Eggermont and Kenmochi1998; Eggermont 2003). Furthermore, quinine, known to generate tinnitus,induces an increased regularity in burst firing, at the level of theauditory cortex, inferior colliculus and frontal cortex (Gopal and Gross2004). It is contemplated that tinnitus can only become conscious if anincreased tonic firing rate is present in the lemniscal system,generating the sound. This increased firing activity has beendemonstrated in the lemniscal dorsal cochlear nucleus (Kaltenbach,Godfrey et al., 1998; Zhang and Kaltenbach 1998; Kaltenbach and Afman2000; Brozoski, Bauer et al., 2002; Zacharek et al., 2002; Kaltenbach etal., 2004), inferior colliculus (Jastreboff and Sasaki 1986; Jastreboff,Brennan et al., 1988; Jastreboff 1990) (Gerken 1996) and primaryauditory cortex (Komiya, 2000). Interestingly, not only tonic firing isincreased generating the tinnitus sound, but also the burst firing (Ochiand Eggermont 1997) (keeping it conscious) at a regular basis.Repetitive burst firing is known to generate tonic gamma band activity(Gray and Singer 1989; Brumberg, 2000). Thus, it is envisioned thatembodiments herein can be used to modify burst firing, thus modifyingtonic gamma activity.

Burst mode firing boosts the gain of neural signaling of important ornovel events by enhancing transmitter release and enhancing dendriticdepolarization, thereby increasing synaptic potentiation. Conversely,single spiking mode may be used to dampen neuronal signaling and may beassociated with habituation to unimportant events (Cooper 2002). It isbelieved that the main problem in tinnitus is that the internallygenerated stimulus does not decay due to the presence of regularbursting activity telling the cortex this signal is important and has toremain conscious.

Thus, in embodiments herein, it is envisioned that the hub stimulationmay be applied to stimulate multiple network nodes to treat tinnitus asdiscussed herein.

In phantom pain the same is noted as in Parkinson's Disease (PD) andtinnitus. In humans, the tonic firing rate increases (Yamashiro et al.,2003), as well as the amount of burst firing in the deafferentedreceptive fields (Rinaldi et al., 1991; Jeanmonod et al., 1996;Radhakrishnan et al., 1999) in the somatosensory thalamic nuclei(Rinaldi et al., 1991; Lenz et al., 1998), as well as activity in the inthe intralaminar nuclei (Weigel and Krauss 2004). Synchrony in firing isalso increased. This is similar to what is seen in animal neuropathicpain models (Lombard and Besson 1989; Nakamura and Atsuta 2004)(Yamashiro et al., 1991). These results suggest that in pain decreasedspike frequency adaptation and increased excitability develops afterinjury to sensory neurons. Through decreased Ca.sup.2+ influx, the cellbecomes less stable and more likely to initiate or transmit bursts ofaction potentials (McCallum et al., 2003).

Thus, it is envisioned that that the neuromodulation system or method ofembodiments herein will alter or disrupt neural activity associated withthe phantom pain.

In Parkinson's disease (PD), the striatum is viewed as the principalinput structure of the basal ganglia, while the internal pallidalsegment (GPi) and the substantia nigra pars reticulata (SNr) are outputstructures. Input and output structures are linked via a monosynaptic“direct” pathway and a polysynaptic “indirect” pathway involving theexternal pallidal segment (GPe) and the subthalamic nucleus (STN).According to current schemes, striatal dopamine (DA) enhancestransmission along the direct pathway (via D1 receptors), and reducestransmission over the indirect pathway (via D2 receptors) (Wichmann andDeLong 2003).

Increased firing rates are noted in PD, both in the globus pallidus(Magnin et al., 2000) and the subthalamic nucleus (Levy et al., 2002)and is reversed in successful STN stimulation in PD (Welter et al.,2004; Boraud et al., 1996). Synchronization between firing rates isimportant: lower frequency oscillations facilitate slow idling rhythmsin the motor areas of the cortex, whereas synchronization at highfrequency restores dynamic task-related cortical ensemble activity inthe gamma band (Brown 2003). In PD, a (hyper)synchronization is relatedto tremor (Levy et al., 2002), similarly to what is seen in the animalParkinson model (Raz et al., 2000; Nini et al., 1995).

Two or more firing modes exist in the subthalamic nucleus: tonic firing(68%), phasic or burst firing (25%) and phasic-tonic (7%)(Magarinos-Ascone et al., 2002).

In the monkey MPTP Parkinson model, burst firing, which occurs at 4 to 8Hz, increases in the STN and Gpi in comparison to normal firing (from69% and 78% in STN and GPi to 79% and 89%, respectively) (Bergman etal., 1994), as well as burst duration, without increase in the amount ofspikes per burst (Bergman et al., 1994). Abnormally increased tonic andphasic activity in STN leads to abnormal GPi activity and is a majorfactor in the development of parkinsonian motor signs (Wichmann et al.,1994). The percentage of cells with 4- to 8-Hz periodic activitycorrelates with tremor and is significantly increased from 2% to 16% inSTN and from 0.6% to 25% in GPi with the MPTP treatment (Bergman et al.,1994). These cells are also recorded in humans with PD (Hutchison etal., 1997). Furthermore, synchronization increases, e.g., a decrease inindependent activity (Raz et al., 2000; Nini et al., 1995), both intonically firing cells (Raz et al., 2001) and burst firing cells. Thus,it is envisioned that that the neuromodulation or stimulation system ormethod of embodiments herein will alter or disrupt or override theregular bursting rhythm associated with PD.

Other movement disorders, for example, chorea, Huntington's chorea,hemiballism and parkinsonian tremor all differ in the amount ofregularity in their muscle contractions. (Hashimoto and Yanagisawa1994). The regularities of interval, amplitude, rise time, and EMGactivity differs within order of regularity, such PD, vascular chorea,Huntington chorea and hemiballism being least regular (Hashimoto andYanagisawa 1994). However, in chorea (Hashimoto et al., 2001),hemiballism (Postuma and Lang 2003) and Huntington's disease (Cubo etal., 2000), the firing rate might be decreased in contrast to PD. Burstdischarges are, however, correlated to the choreatic movements (Kanazawaet al., 1990), similarly to what is noted in PD (Bergman, Wichmann etal., 1994). Thus, the neuromodulation system and/or method ofembodiments herein is used to alter or disrupt neural activityassociated with the neurological motor disorder, disease, or condition.

Food presentation in normal healthy, non-obese individuals significantlyincreases metabolism in the whole brain (24%, P<0.01), and these changesare largest in superior temporal, anterior insula, and orbitofrontalcortices (Wang, Volkow et al., 2004). Food-related visual stimuli elicitgreater responses in the amygdala, parahippocampal gyms and anteriorfusiform gyms when participants are in a hungry state relative to asatiated state (LaBar, Gitelman et al., 2001). Hunger is associated withsignificantly increased rCBF in the vicinity of the hypothalamus andinsular cortex and in addition paralimbic and limbic areas(orbitofrontal cortex, anterior cingulate cortex, and parahippocampaland hippocampal formation), thalamus, caudate, precuneus, putamen, andcerebellum (Tataranni, Gautier et al., 1999). Satiation is associatedwith increased rCBF in the vicinity of the ventromedial prefrontalcortex, dorsolateral prefrontal cortex, and inferior parietal lobule(Tataranni, Gautier et al., 1999). High-calorie foods yield significantactivation within the medial and dorsolateral prefrontal cortex,thalamus, hypothalamus, corpus callosum, and cerebellum. Low-caloriefoods yield smaller regions of focal activation within medialorbitofrontal cortex, primary gustatory/somatosensory cortex, andsuperior, middle, and medial temporal regions (Killgore, Young et al.,2003). Activity within the temporo-insular cortex in normal appetitivefunction is associated with the desirability or valence of food stimuli,prior to ingestion (Gordon, Dougherty et al., 2000). When a food iseaten to satiety, its reward value decreases. Responses of gustatoryneurons in the secondary taste area within the orbitofrontal cortex aremodulated by hunger and satiety, in that they stop responding to thetaste of a food on which an animal has been fed to behavioral satiation,yet may continue to respond to the taste of other foods (Critchley andRolls 1996; O'Doherty, Rolls et al., 2000). In the OFC, the rCBFdecreases in the medial OFC and increases in the lateral OFC as thereward value of food changes from pleasant to aversive for non-liquid(Small, Zatorre et al., 2001) and liquid foods (Kringelbach, O'Dohertyet al., 2003). In the insular gustatory cortex, neuronal responses togustatory stimuli are not influenced by the normal transition fromhunger to satiety. This is in contrast to the responses of a populationof neurons recorded in the hypothalamus, which only respond to the tasteof food when the monkey is hungry (Yaxley, Rolls et al., 1988).

Brain responses to hunger/satiation in the hypothalamus,limbic/paralimbic areas (commonly associated with the regulation ofemotion), and prefrontal cortex (thought to be involved in theinhibition of inappropriate response tendencies) might be different inobese and lean individuals (Del Parigi, Gautier et al., 2002). Comparedwith lean women, obese women have significantly greater increases inrCBF in the ventral prefrontal cortex and have significantly greaterdecreases in the paralimbic areas and in areas of the frontal andtemporal cortex (Gautier, Del Parigi et al., 2001). In obese women, therCBF is higher in the right parietal and temporal cortices during thefood exposure than in the control condition. In addition, in obese womenthe activation of the right parietal cortex is associated with anenhanced feeling of hunger when looking at food (Karhunen, Lappalainenet al., 1997). This significantly higher metabolic activity in thebilateral parietal somatosensory cortex is noted in the regions wheresensation to the mouth, lips and tongue are located. The enhancedactivity in somatosensory regions involved with sensory processing offood in the obese subjects can make them more sensitive to the rewardingproperties of food related to palatability and can be one of thevariables contributing to their excess food consumption (Wang, Volkow etal., 2002).

The neuromodulation system and/or method of embodiments herein is usedto alter or disrupt the neural activity related to eating disorders in apatient.

Cognitive and psychological disorders In patients suffering from adepression, a hypometabolism and hypoperfusion localized to the leftmiddorsolateral frontal cortex (MDLFC) is noted (Baxter, Schwartz etal., 1989; Brody, Saxena et al., 2001). Furthermore decreased neuralactivity in the MDLFC, aka the dorsolateral prefrontal cortex, iscorrelated with severity of depression (Bench, Friston et al., 1992;Bench, Friston et al., 1993; Dolan, Bench et al., 1994) and is reversedupon recovery from depression (Bench, Frackowiak et al., 1995).Electroencephalography demonstrates increased alpha power. Alpha poweris thought to be inversely related to neural activity in left frontalregions of the brains of depressed patients (Bruder, Fong et al., 1997).

Metabolic activity in the ventral perigenual ACC is increased indepressed patients relative to control subjects (Videbech, Ravnkilde etal., 2001) and is positively correlated with severity of depression(Drevets 1999). Furthermore, neural activity in this region decreases inresponse to antidepressant treatment (Brody, Saxena et al., 2001).

The MDLFC occupies the middle frontal and superior frontal gyri andcomprises cytoarchitectonic areas 46 and 9/46 (middle frontal gyms) andarea 9 (superior frontal gyms) (Paus and Barrett 2004). The MDLFC hasconnections with sensory areas processing visual (prestriate andinferior temporal cortices), auditory (superior temporal cortex) andsomatosensory (parietal cortex) information (Petrides and Pandya 1999).The MDLFC also reciprocally connects with the anterior and, to a lesserextent, posterior cingulate cortices (Bates and Goldman-Rakic 1993).

Transcranial magnetic stimulation has been performed in the treatment ofdepression. The left MDLFC is the most common target for rTMS treatmentof depression (Paus and Barrett 2004), and rTMS of the left MDLFCmodulates the blood-flow response in the ACC (Barrett, Della-Maggiore etal., 2004; Paus and Barrett 2004). High-frequency (20 Hz) andlow-frequency (1 Hz) stimulation seem to have an opposite effect.High-frequency stimulation (HFS) increases and low-frequency stimulation(LFS) decreases cerebral blood flow (CBF) and/or glucose metabolism inthe frontal cortex and other linked brain regions (Speer, Kimbrell etal., 2000; Kimbrell, Little et al., 1999; and Post, Kimbrell et al.,1999).

Successful treatment of depression with TMS results in normalization ofhypoperfusion (with HFS) and normalization hyperperfusion (with LFS)(Kimbrell, Little et al., 1999). Thus, TMS treatment for depression canbe proposed using 20 Hz left frontal cortex (Kimbrell, Little et al.,1999; Paus and Barrett 2004) or 1 Hz right frontal cortex (Klein,Kreinin et al., 1999).

In the ACC of the rat, three kinds of burst firing is recorded. Rhythmicburst firing with inter-burst intervals of 80 and 200 ms andnon-rhythmic burst firing (Gemmell, Anderson et al., 2002). ACCstimulations evoke both tonic and burst reactions in the dorsolateralprefrontal cortex (Desiraju 1976). Similarly to other cortical areas,the dorsolateral prefrontal cortex has burst firing cells, tonic firingcells and mixed firing cells. Similarly to other areas, the burst firingnotices new incoming sensory (auditory, visual) information, and tonicfiring continues as long as the stimulus lasts (Ito 1982). TMS in burstmode is more powerful than TMS in tonic mode. For example, 20 seconds of5 Hz burst firing with 3 pulses at 50 Hz per burst have the same effectas 10 minutes 1 Hz tonic TMS.

Obsessive-compulsive disorder is a worldwide psychiatric disorder with alifetime prevalence of 2% and mainly characterized by obsessional ideasand compulsive behaviors and rituals. Bilateral stimulation in theanterior limbs of the internal capsules (Nuttin, Cosyns et al., 1999;Nuttin, Gabriels et al., 2003) or nucleus accumbens stimulation (Sturm,Lenartz et al., 2003) can improve symptoms but at high frequency andhigh intensity stimulation.

Tourette syndrome (TS) is a neuropsychiatric disorder with onset inearly childhood. It is characterized by tics and often accompanied bydisturbances in behavior, such as obsessive-compulsive disorder (OCD).Bilateral thalamic stimulation, with promising results on tics andobsessive-compulsive symptoms has been performed as a treatment.(Visser-Vandewalle, Temel et al., 2003; Temel and Visser-Vandewalle2004).

The neuromodulation system and/or method of embodiments herein is usedto alter or disrupt the neural activity related to mood and/or anxietydisorders in a patient.

One or more of the operations described above in connection with themethods may be performed using one or more processors. The differentdevices in the systems described herein may represent one or moreprocessors, and two or more of these devices may include at least one ofthe same processors. In one embodiment, the operations described hereinmay represent actions performed when one or more processors (e.g., ofthe devices described herein) execute program instructions stored inmemory (for example, software stored on a tangible and non-transitorycomputer readable storage medium, such as a computer hard drive, ROM,RAM, or the like).

The processor(s) may execute a set of instructions that are stored inone or more storage elements, in order to process data. The storageelements may also store data or other information as desired or needed.The storage element may be in the form of an information source or aphysical memory element within the controllers and the controllerdevice. The set of instructions may include various commands thatinstruct the controllers and the controller device to perform specificoperations such as the methods and processes of the various embodimentsof the subject matter described herein. The set of instructions may bein the form of a software program. The software may be in various formssuch as system software or application software. Further, the softwaremay be in the form of a collection of separate programs or modules, aprogram module within a larger program or a portion of a program module.The software also may include modular programming in the form ofobject-oriented programming. The processing of input data by theprocessing machine may be in response to user commands, or in responseto results of previous processing, or in response to a request made byanother processing machine.

The controller may include any processor-based or microprocessor-basedsystem including systems using microcontrollers, reduced instruction setcomputers (RISC), application specific integrated circuits (ASICs),field-programmable gate arrays (FPGAs), logic circuits, and any othercircuit or processor capable of executing the functions describedherein. When processor-based, the controller executes programinstructions stored in memory to perform the corresponding operations.Additionally or alternatively, the controllers and the controller devicemay represent circuits that may be implemented as hardware. The aboveexamples are exemplary only, and are thus not intended to limit in anyway the definition and/or meaning of the term “controller.”

It is to be understood that the subject matter described herein is notlimited in its application to the details of construction and thearrangement of components set forth in the description herein orillustrated in the drawings hereof. The subject matter described hereinis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, it is to be understood that thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having” and variations thereof herein ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items.

It is to be understood that the above description is intended to beillustrative, and not restrictive. For example, the above-describedembodiments (and/or aspects thereof) may be used in combination witheach other. In addition, many modifications may be made to adapt aparticular situation or material to the teachings of the inventionwithout departing from its scope. While the dimensions, types ofmaterials and coatings described herein are intended to define theparameters of the invention, they are by no means limiting and areexemplary embodiments. Many other embodiments will be apparent to thoseof skill in the art upon reviewing the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled. In the appended claims, the terms “including” and“in which” are used as the plain-English equivalents of the respectiveterms “comprising” and “wherein.” Moreover, in the following claims, theterms “first,” “second,” and “third,” etc. are used merely as labels,and are not intended to impose numerical requirements on their objects.Further, the limitations of the following claims are not written inmeans—plus-function format and are not intended to be interpreted basedon 45 U.S.C. § 112(f), unless and until such claim limitations expresslyuse the phrase “means for” followed by a statement of function void offurther structure.

What is claimed is:
 1. A method to deliver nested stimulation to nervetissue of interest, the method comprising: setting first parameters thatdefine a carrier waveform, wherein the carrier waveform exhibits awaveform frequency of less than 1 Hz; setting second parameters thatdefine a high frequency waveform, wherein at least one of the carrierwaveform and high frequency waveform are defined to correspond tophysiologic neural oscillations associated with the nerve tissue ofinterest; operating a pulse generator to generate a nested stimulationwaveform that combines the carrier waveform and high frequency waveform,the nested stimulation waveform having a plurality of pulse bursts; anddelivering the nested stimulation waveform through one or moreelectrodes to the nerve tissue of interest.
 2. The method of claim 1,wherein the nerve tissue of interest includes brain tissue of interest,and wherein the high frequency waveform corresponding to high-frequencyphysiologic neural oscillations associated with brain tissue ofinterest, and herein the pulse bursts including pulses having afrequency corresponding to the high frequency neural oscillations. 3.The method of claim 1, wherein the carrier waveform exhibits anfrequency of 0.01 Hz.
 4. The method of claim 3, wherein the pulse burstsare separated from one another with a burst to burst period thatcorresponds to a frequency of the low-frequency neural oscillations. 5.The method of claim 1, wherein the first and second parameters define atleast one of an amplitude, burst to burst frequency, pulse frequency,pulse width, burst length and burst period for the plurality of pulsebursts.
 6. The method of claim 1, further comprising combining thecarrier and high-frequency waveforms utilizing one of the followingtypes of cross frequency coupling: power to power; phase to power; phaseto phase; phase to frequency; power to frequency and frequency tofrequency.
 7. The method of claim 1, wherein the carrier andhigh-frequency waveforms are combined through phase to power crossfrequency coupling, in which the phase of the carrier waveform modulatesthe power of the high-frequency waveform.
 8. The method of claim 1,wherein the first parameters are set to define the carrier waveform tocorrespond to the theta wave frequency band, while the second parametersare set to define the high-frequency waveform to correspond to the gammawave frequency band, the method further comprising managing the nestedstimulation waveform modulating the neural oscillations in the gammawave frequency band in connection with at least one of sensory, motor,and cognitive events.
 9. The method of claim 1, wherein the nerve tissueof interest includes brain tissue of interest, and further comprisingmanaging the nested stimulation waveform in connection with an event ofinterest through cross frequency coupling between theta and gamma wavesassociated with brain tissue of interest.
 10. The method of claim 1,wherein the nerve tissue of interest includes brain tissue of interest,and wherein the brain tissue of interest comprises distributed neuralmodules located in separate regions of the brain, the method furthercomprising managing the nested stimulation waveform in connection withcross frequency coupling between neural oscillations associated with thedistributed neural modules that exhibit long-distance communication overneural oscillations within at least one of delta, theta and alpha wavefrequency bands
 11. A method of treating a neurological disorder in apatient, comprising: identifying a neural network in the brain of thepatient related to the neurological disorder; identifying at least twoseparate target sites in the neural network for stimulation, wherein theat least two separate target sites include a hub site within the neuralnetwork; providing one or more stimulation leads with electrodespositioned relative to the at least two separate target sites; providingelectrical stimulation to the at least two separate target sites toadjust functional connectivity between the at least two separate targetsites to treat the neurological disorder, wherein the electricalstimulation exhibits a carrier wave frequency of less than 1 Hz.
 12. Themethod of claim 11 wherein the providing electrical stimulationcomprises: repeatedly providing respective electrical pulses to the atleast two separate target sites in a synchronized manner to strengthenfunctional connectivity between the at least two separate target sites.13. The method of claim 11 wherein the providing electrical stimulationcomprises: providing electrical stimulation to the at least two separatetarget sites in a pseudo-random manner to weaken functional connectivitybetween the at least two separate target sites.
 14. The method of claim11, wherein the electrical stimulation exhibits a carrier wave frequencyof 0.01 Hz.